Difluorolactam compositions for ep4-mediated osteo related diseases and conditions

ABSTRACT

Disclosed herein are compositions and methods of treating osteoporosis, bone fracture, bone loss, and increasing bone density by administration of compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     or compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, wherein L 1 , L 2 , L 4 , R 1 , R 4 , R 5 , R 6 , and s are as defined in the specification.

FIELD OF THE INVENTION

The subject matter disclosed and claimed herein centers on novel EP₄receptor-selective 3,3-difluoropyrrolidin-2-one (γ-lactam) derivativesand their uses as therapies for EP₄ receptor-mediated diseases andconditions.

BACKGROUND OF THE INVENTION

All references, including patents and patent applications, are herebyincorporated by reference in their entireties.

Arachidonic acid (abbreviated as AA herein) is a ubiquitouspolyunsaturated fatty acid (PUFA) that is found esterified tophospholipids at the secondary alcohol of glycerol in all mammaliancellular membranes. Enzymatic hydrolysis of esterified AA by calcium(Ca²⁺)-induced cytosolic phospholipase 2 (cPLA2) releases free AA, whichmay be further catalytically converted by the cyclooxygenase (COX) intothe intermediate prostaglandin H2 followed by subsequent enzymaticisomerization into the naturally occurring prostaglandins (PGs) andthromboxanes. The five primary prostanoids include prostaglandin F_(2α)(PGF_(2α)), prostaglandin D₂ (PGD₂), prostaglandin I₂ (PGI₂),thromboxane A₂ (TxA₂), and prostaglandin E₂ (PGE₂), (Jahn, U. et al.,Angew. Chem. Int. Ed. 2008, 47, 5894-5955; Wymann, M. P. et al., Nat.Rev. Mol. Cell. Biol. 2008, 9, 162-176; Samuelsson, B. et al., Ann. Rev.Biochem. 1978, 47, 997-1029). These five prostaglandins are lipidmediators that interact with nine specific members of a distinctprostanoid subfamily of G-protein-coupled receptors (GPCRs), designatedFP, DP₁₋₂, IP, TP, and EP₁₋₄, respectively (Breyer, R. M. et al., Annu.Rev. Pharmacol. Toxicol. 2001, 41, 661-690). Prostaglandin and PGreceptor pharmacology, signaling, and physiology have been studied andwell documented (Hata, A. N. et al., Pharmacol. Ther. 2004, 103(2),147-166; ElAttar, T. M. A., J. Oral Pathol. Med. 1978, 7(5), 239-252;Poyser, N. L., Clinics in Endocrinology and Metabolism 1973, 2(3),393-410). Prostaglandins are short-lived local signaling molecules thatare not stored in cells or tissues but are produced as needed byspecific cells of virtually all body tissues. Their target cells residein the immediate vicinity of their secretion sites. Well-known PGfunctions include regulation of cell stimulation, growth, anddifferentiation, immune response and inflammation, allergy, asthma,pain, vasomotor action, neuromodulation, intraocular pressure, andplatelet aggregation, as well as mediation of fever, managing of renalblood flow, and induction of labor (Negishi, M. et al., Prog. Lipid Res.1993, 32(4), 417-434).

As is the case for most prostaglandins, the biosynthesis of PGE₂commences with liberation of free AA from its esterified form in thecell membrane. One key enzyme involved in PGE₂ biosynthesis isprostaglandin H synthase (PGHS). PGHS possesses both a COX and aperoxidase function. The COX activity promotes conversion of free AA tothe unstable endoperoxide prostaglandin G₂ (PGG₂) via double oxygeninsertion. One inserted oxygen molecule is subsequently reduced by theperoxidase activity of PGHS to provide the versatile biosyntheticcascade intermediate PGH₂. The glutathione-dependent enzymeprostaglandin E synthase (PGES) promotes isomerization of PGH₂ to PGE₂via peroxide ring opening of PGH₂ to provide the highly functionalizedhydroxypentanone scaffold of PGE₂.

The physiology of PGE₂ and the pharmacology of its four knowncomplementary receptor subtypes designated EP₁, EP₂, EP₃, and EP₄ areamong the most widely studied and published fields of PG research(Sugimoto, Y. et al., J. Biol. Chem. 2007, 282(16), 11613-11617; Suzuki,J. et al., Prostaglandins 2010, 127-133; Regan, J. et al., Life Sciences2003, 74(2-3), 143-153; Bouayad, A. et al., Current Ther. Res. 2002,63(10), 669-681; Breyer, M. et al., Kidney Int., Suppl. 1998, 67,S88-S94; Breyer, M. et al., Amer. J. Physiol. 2000, 279(1, Part 2),F12-F23; Negishi, M. et al., Recent Res. Dev. Endocrinol. 2000, 1(1),133-143; Ma, W. et al., Prog. Inflamm. Res. 2006, 39-93; Mutoh, M. etal., Current Pharmaceutical Design 2006, 12(19), 2375-2382; Hebert, R.et al., Current Topics in Pharmacology 2002, 6, 129-137; Coleman, R. etal., Pharm. Rev. 1994, 46(2), 205-229). PGE₂ binds to each of the fourEP receptors with high affinity (Anderson, L. et al., Journal ofReproduction and Fertility, 1999, 116, 133-141). The prostaglandin PGE₁(saturated α-chain analog of PGE₂), the major eicosanoid synthesizedbiologically from dihomo-γ-linolenic acid (DGLA) in response to variousstimuli, also binds efficiently to all four EP receptor subtypes.

The EP₄ receptor is expressed in a wide variety of tissues includingthose of the skeletal, muscular, central and peripheral nervous, immune,respiratory, cardiovascular, digestive, excretory, and reproductivetissues and is known to be involved in such processes and conditions asbone growth and remodeling, osteoporosis, relaxation of smooth muscle,neuroprotection, ocular inflammation, immune response, and cancer.Modulation of the EP₄ receptor may also be involved in the neonataldevelopment of the circulatory system (Fan, F. et al., Clinical andExperimental Pharmacology and Physiology, 2010, 37, 574-580; Bouayad, A.et al., Current Ther. Res. 2002, 63(10), 669-681; Bouayad, A. et al.,Am. J. Physiol. Heart Circ. Physiol. 2001, 280, H2342-H2349). Activationof the EP₄ receptor by PGE₂ increases intracellular cAMP levels, leadingto downstream effects associated with antiapoptotic activity andcytoprotection (Fujino, H. and Regan, J., Trends in PharmacologicalSciences, 2003, 24(7), 335-340; Hoshino, T. et al., J. Biol. Chem.,2003, 278(15), 12752-12758; Takahashi, S. et al., Biochem. Pharmacol.,1999, 58(12), 1997-2002; Quiroga, J. et al., Pharmacol. Ther., 1993,58(1), 67-91).

EP₄ receptor agonists are reported to be useful in lowering intraocularpressure and to have application in treating glaucoma. Prasanna, G. etal., Exp. Eye Res., 2009, 89 (5), 608-17; Luu, K. et al., J. Pharmacol.Exp. Ther. 2009, 331(2), 627-635; Saeki, T. et al, Invest. Ophthalmol.Vis. Sci., 2009, 50 (5) 2201-2208.

EP₄ receptor agonists are also reported to induce bone remodeling and tohave use in the treatment of osteoporosis. Iwaniec, U. et al.,Osteoporosis International, 2007, 18 (3), 351-362; Aguirre, J. et al.,J. Bone and Min. Res., 2007, 22(6), 877-888; Yoshida, K. et al., Proc.Natl. Acad. Sci. USA, 2002, 99 (7), 4580-4585. Hayashi, K. et al., J.Bone Joint Surg. Br., 2005, 87-B (8), 1150-6.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

L¹ is

a) C₃-C₇alkylene, C₃-C₇alkenylene, or C₃-C₇alkynylene, wherein theC₃-C₇alkylene, C₃-C₇alkenylene, or C₃-C₇alkynylene are each optionallysubstituted with 1, 2, 3, or 4 fluoro substituents;

b) —(CH₂)_(t)-G-(CH₂)_(p)—; wherein t is 0, 1, or 2, p is 0, 1, 2, or 3,and t+p=0, 1, 2, 3, or 4; or

c) —(CH₂)_(n)-G¹-(CH₂)_(p)—, —(CH₂)_(n)-G²-(CH₂)_(p)—,—(CH₂)_(n)—C≡C-G²-, or —(CH₂)_(n)—C(R¹³)═C(R³)-G²-, wherein n is 1, 2,3, 4, or 5, p is 0, 1, 2, or 3, and n+p=1, 2, 3, 4, 5, or 6;

G is

G¹ is O, C(O), S, S(O), S(O)₂, or NR⁸; wherein R⁸ is H, C₁-C₄ alkyl, orC₁-C₄alkylcarbonyl;

G is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy;

R¹ is COOR¹⁰, CONR¹⁰R¹¹, CH₂OR¹⁰, SO₃R¹⁰, SO₂NR¹⁰R¹¹, PO(OR¹⁰)₂, ortetrazol-5-yl;

R¹⁰ is H, C₁-C₄ alkyl, or aryl;

R¹¹ is H, C₁-C₄ alkyl, COR¹², OR¹⁰, or SO₂R¹²;

R¹² is C₁-C₄ alkyl;

R¹³, at each occurrence, is independently H or C₁-C₄alkyl;

L⁴ is —C(R²)₂—C(R³)₂—, —C(R²)═C(R³)—, —C≡C—, or

wherein R² and R³ are each H, CH₃, fluoro, or chloro;

L² is —CH₂— or a bond;

R⁴ and R⁵ are each independently H, F, CF₃, or C₁-C₄ alkyl; or R⁴ and R⁵together with the carbon to which they are attached form a C₃-C₅cycloalkyl,

R⁶ is aryl, heteroaryl, C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, C₃-C₁₀haloalkynyl, or L³-R⁷; whereinthe aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₄alkyl,C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy; and—C₁-C₃alkylene-C₁-C₃alkoxy; and wherein the C₃-C₁₀alkyl, C₃-C₁₀alkenyl,C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, and C₃-C₁₀haloalkynylare optionally substituted with a substituent selected from the groupconsisting of COOR^(10′), CONR^(10′)R^(11′), CH₂OR^(10′), SO₃R^(10′),SO₂NR^(10′)R^(11′), PO(OR^(10′))₂, and tetrazol-5-yl;

R^(10′) is H, C₁-C₄ alkyl, or aryl;

R^(11′) is H, C₁-C₄ alkyl, COR^(12′), OR^(10′), or SO₂R^(12′);

R^(12′) is C₁-C₄ alkyl;

L³ is C₁-C₆alkylene, C₂-C₆alkenylene, C₂-C₆alkynylene,—(CH₂)_(m)-G³-(CH₂)_(q)—, —(CH₂)_(m)-G⁴-(CH₂)_(q)—, or -G⁵-C≡C—; whereinthe C₁-C₆alkylene, C₂-C₆alkenylene, and C₂-C₆alkynylene are optionallysubstituted with 1, 2, 3, or 4 fluoro substituents; and wherein m and qare each independently 0, 1, 2, or 3 and m+q=0, 1, 2, 3, or 4;

G³ is O, C(O), S, S(O), S(O)₂, or NR⁹; wherein R⁹ is H, C₁-C₄ alkyl, orC₁-C₄alkylcarbonyl;

G⁴ is

wherein G⁴ is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy;

G⁵ is

wherein G⁵ is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy;

R⁷ is C₃-C₈cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein R⁷ isoptionally substituted with 1, 2, 3, or 4 substituents selected from thegroup consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy;

r is 0 or 1; and

s is 0 or 1.

In another aspect, the present invention provides compounds of formula(Ia)

or a pharmaceutically acceptable salt thereof, wherein R¹, R⁴, R⁵, R⁶,L¹, L², L⁴, and s are as defined herein.

In another aspect of the invention are compounds of formula (II)

or a pharmaceutically acceptable salt thereof, wherein R¹, R⁴, R⁵, R⁶,and L¹ are as defined herein.

Another aspect of the present invention relates to pharmaceuticalcompositions comprising therapeutically effective amounts of a compounddescribed herein or a pharmaceutically acceptable salt, solvate, salt ofa solvate, or solvate of a salt thereof, in combination with apharmaceutically acceptable carrier.

In another aspect, the invention provides compounds that bind to the EP₄receptor with high affinity and agonist activity. In certainembodiments, compounds of the invention may possess selectivity for theEP₄ receptor versus other EP receptors.

In another aspect, the present invention provides a method of treating adisease or disorder related to the EP₄ receptor by administering to apatient a therapeutically effective amount of a compound or compositionof formula (I), (Ia), or (II). Such diseases or disorders include thoserelated to elevated intraocular pressure such as glaucoma. Otherdiseases or conditions treatable by the compounds and compositions ofthe invention include those associated with excessive bone loss, such asosteoporosis.

The present invention also provides methods of preparing compounds offormula (I), (IA), or (II).

In another aspect, the invention provides intermediates useful in thepreparation of EP₄ agonists. In still another aspect, the inventionprovides methods of preparing the intermediates.

Further provided herein are the use of the present compounds orpharmaceutically acceptable salts, solvates, salts of solvates, orsolvates of salts thereof, in the manufacture of a medicament for thetreatment of the diseases or conditions described herein, alone or incombination with one or more pharmaceutically acceptable carrier(s).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts data showing the effect of Compound 2C on stimulation ofbone growth in the rat calvarial defect model.

DETAILED DESCRIPTION Definition of Terms

The term “agonist” as used herein refers to a compound, the biologicaleffect of which is to mimic the action of the natural agonist PGE2. Anagonist may have full efficacy (i.e., equivalent to PGE2), partialefficacy (lower maximal efficacy compared to PGE2), or super maximalefficacy (higher maximal efficacy compared to PGE2). An agonist withpartial efficacy is referred to as a “partial agonist.” An agonist withsuper maximal efficacy is referred to as a “super agonist.”

The term “alkyl” as used herein, means a straight or branched chainsaturated hydrocarbon. Representative examples of alkyl include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, and n-decyl.

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon and containing at least one carbon-carbon double bond.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkynyl,” as used herein, means a straight or branched chainhydrocarbon and containing at least one carbon-carbon triple bond.Representative examples include propynyl, butynyl, pentynyl, and thelike.

The term “alkylene,” as used herein, means a divalent group derived froma straight or branched chain hydrocarbon. Representative examples ofalkylene include, but are not limited to, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH(CH₃)CH₂—, and —CH₂CH(CH₃)CH(CH₃)CH₂—.

The term “alkenylene,” as used herein, means a divalent group derivedfrom a straight or branched chain hydrocarbon and containing at leastone carbon-carbon double bond. Representative examples of alkenyleneinclude, but are not limited to —CH═CH—, —CH₂CH═CH—, and—CH₂CH═CH(CH₃)—.

The term “alkynylene,” as used herein, means a divalent group derivedfrom a straight or branched chain hydrocarbon and containing at leastone carbon-carbon triple bond. Representative examples of alkynyleneinclude, but are not limited to —CH₂—C≡C—, —CH₂CH₂—C≡C—, and—C≡C—CH₂CH(CH₃)CH₂—.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,pentyloxy, and hexyloxy.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through a C(O)group.

The terms “haloalkyl,” “haloalkenyl,” and “haloalkynyl” as used herein,mean, respectively an alkyl, alkenyl, or alkynyl group, as definedherein, in which one, two, three, four, five, six, or seven hydrogenatoms are replaced by halogen. For example, representative examples ofhaloalkyl include, but are not limited to, 2-fluoroethyl,2,2-difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl,2,2,2-trifluoro-1,1-dimethylethyl, and the like.

The term “haloalkoxy,” as used herein, means an alkoxy group, as definedherein, in which one, two, three, four, five, or six hydrogen atoms arereplaced by halogen. Representative examples of haloalkoxy include, butare not limited to, trifluoromethoxy, difluoromethoxy,2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, andpentafluoroethoxy.

The term “aryl,” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl,indanyl, or indenyl. The phenyl and bicyclic aryls are attached to theparent molecular moiety through any carbon atom contained within thephenyl or bicyclic aryl.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora fused bicyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6membered ring containing at least one heteroatom independently selectedfrom the group consisting of O, N, and S. The 5-membered ring containstwo double bonds, and one, two, three, or four heteroatoms as ringatoms. The 6-membered ring contains three double bonds, and one, two,three or four heteroatoms as ring atoms. Representative examples ofmonocyclic heteroaryl include, but are not limited to, furanyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclicheteroaryl is an 8- to 12-membered ring system having a monocyclicheteroaryl fused to an additional ring; wherein the additional ring maybe aromatic or partially saturated, and may contain additionalheteroatoms. Representative examples of bicyclic heteroaryl include, butare not limited to, benzofuranyl, benzoxadiazolyl, 1,3-benzothiazolyl,benzimidazolyl, benzodioxolyl, benzothienyl, chromenyl, furopyridinyl,indolyl, indazolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine,quinolinyl, thienopyridinyl, 5,6,7,8-tetrahydroquinolinyl,6,7-dihydro-5H-cyclopenta[b]pyridinyl, and2,3-dihydrofuro[3,2-b]pyridinyl. The monocyclic and the bicyclicheteroaryl groups are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the groups.

The term “cycloalkyl” as used herein, means a carbocyclic ring systemcontaining 3, 4, 5, 6, 7, or 8 carbon atoms and zero heteroatoms as ringatoms, and zero double bonds. Examples of cycloalkyls include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The cycloalkyl groups of the presentinvention may contain an alkylene bridge of 1, 2, 3, or 4 carbon atoms,linking two non adjacent carbon atoms of the group. Examples of suchbridged systems include, but are not limited to, bicyclo[2.2.1]heptanyland bicyclo[2.2.2]octanyl. The cycloalkyl groups described herein can beappended to the parent molecular moiety through any substitutable carbonatom.

The term “heterocycle” or “heterocyclic” as used herein, refers to amonocyclic heterocycle, a bicyclic heterocycle, or a spirocyclicheterocycle. The monocyclic heterocycle is a 3, 4, 5, 6, 7, or8-membered ring containing at least one heteroatom selected from O, N,or S. The 3 or 4 membered ring contains one heteroatom and optionallyone double bond. The 5-membered ring contains zero or one double bondand one, two or three heteroatoms. The 6, 7, or 8-membered ring containszero, one, or two double bonds, and one, two, or three heteroatoms.Representative examples of monocyclic heterocycle include, but are notlimited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, 4,5-dihydroisoxazol-5-yl,3,4-dihydropyranyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl,thiopyranyl, and trithianyl. The bicyclic heterocycle is a 5-12-memberedring system having a monocyclic heterocycle fused to a phenyl, asaturated or partially saturated carbocyclic ring, or another monocyclicheterocyclic ring. Representative examples of bicyclic heterocycleinclude, but are not limited to, 1,3-benzodioxol-4-yl,1,3-benzodithiolyl, 3-azabicyclo[3.1.0]hexanyl,hexahydro-1H-furo[3,4-c]pyrrolyl, 2,3-dihydro-1,4-benzodioxinyl,2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl,2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl. Spirocyclicheterocycle means a 4, 5-, 6-, 7-, or 8-membered monocyclic heterocyclering wherein two of the substituents on the same carbon atom form a 3-,4-, 5-, or 6-membered monocyclic ring selected from the group consistingof cycloalkyl and heterocycle, each of which is optionally substitutedwith 1, 2, 3, 4, or 5 alkyl groups. Examples of a spiroheterocycleinclude, but are not limited to, 5-oxaspiro[3,4]octane and8-azaspiro[4.5]decane. The monocyclic and bicyclic heterocycle groups ofthe present invention may contain an alkylene bridge of 1, 2, 3, or 4carbon atoms, linking two non-adjacent atoms of the group. Examples ofsuch a bridged heterocycle include, but are not limited to,2-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.2]octanyl,1,2,3,4-tetrahydro-1,4-methanoisoquinolinyl, andoxabicyclo[2.2.1]heptanyl. The monocyclic, bicyclic, and spirocyclicheterocycle groups are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the group.

Terms such as “alkyl,” “cycloalkyl,” “alkylene,” etc. may be preceded bya designation indicating the number of atoms present in the group in aparticular instance (e.g., “C₃-C₁₀alkyl,” “C₃-C₁₀cycloalkyl,”“C₂-C₆alkynylene,” “C₂-C₆alkenylene”). These designations are used asgenerally understood by those skilled in the art. For example, therepresentation “C” followed by a subscripted number indicates the numberof carbon atoms present in the group that follows. Thus, “C₃alkyl” is analkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where arange is given, as in “C₃-C₁₀,” the members of the group that followsmay have any number of carbon atoms falling within the recited range. A“C₃-C₁₀alkyl,” for example, is an alkyl group having from 3 to 10 carbonatoms, however arranged.

Compounds

According to a general aspect of the present invention, there areprovided compounds useful as EP₄ receptor agonists, as well ascompositions and methods relating thereto. Compounds of the inventionhave the structure set forth in formula (I), (Ia), or (II).

Formula (I) refers to compounds having either β stereochemistry or asubstantially equal mixture of β and α stereochemistries at theγ-position of the lactam ring. Excluded are compounds having pure orsubstantially pure α stereochemistry at the γ-position, as compoundspossessing the α stereochemistry at the γ-position have been found tolack appreciable activity as EP₄ receptor agonists.

In some embodiments of the invention, L¹ is C₃-C₇alkylene,C₃-C₇alkenylene, or C₃-C₇alkynylene, wherein the C₃-C₇alkylene,C₃-C₇alkenylene, or C₃-C₇alkynylene are each optionally substituted with1, 2, 3, or 4 fluoro substituents. In other embodiments, L¹ isC₃-C₇alkylene, optionally substituted. In some groups of compounds, L¹is n-pentylene, n-hexylene, or n-heptylene each optionally substitutedwith 1, 2, 3, or 4 fluoro substituents. In subgroups of compounds, L¹ isn-hexylene.

In other embodiments, L¹ is —(CH₂)_(t)-G-(CH₂)_(p)—; wherein t, p, and Gare as defined herein. In some groups of compounds, t and p are both 0.In other groups of compounds, t is 0 and p is 0, 1, 2, or 3. In stillother groups of compounds, p is 0 and t is 0, 1, or 2.

In other embodiments, L¹ is —(CH₂)_(n)-G¹-(CH₂)_(p)—, wherein G¹ is asdefined herein, n is 1, 2, 3, 4, or 5 and p is 1, 2, or 3.

In still other embodiments, L¹ is —(CH₂)_(n)-G²-(CH₂)_(p)—,—(CH₂)_(n)—C≡C-G²-, or —(CH₂)_(n)—C(H)═C(H)-G²- wherein G², n and p areas defined herein.

In still other embodiments, L¹ is —(CH₂)₃-G²-(CH₂)_(p)—, —CH₂—C≡C-G²-,or —CH₂—C(H)═C(H)-G²-.

In still other embodiments, L¹ is —(CH₂)₃-G²-, —CH₂—C≡C-G²-, or—CH₂—C(H)═C(H)-G²-.

In some embodiments L¹ is —(CH₂)_(n)-G²-(CH₂)_(p)—. For example, in somegroups of compounds, G² is

n is 2 and p is 0. In other groups, G² is

n is 3 and p is 0. In still other groups, G² is

n is 2 and p is 0, 1, 2, or 3. In yet other groups, G² is

p is 0, and n is 2, 3, 4, or 5. In some subgroups, G² is

n is 2 and p is 0. In other subgroups, G² is

n is 3 and p is 0. In other subgroups, G² is

n is 1 and p is 1.

In still other embodiments, L¹ is —(CH₂)_(n)—C≡C-G²- or—(CH₂)_(n)—C(H)═C(H)-G²-. For example, in some groups of compounds G² is

and n is 1. In certain subgroups of compounds G² is

and n is 1. In other subgroups, L¹ is —(CH₂)_(n)—C≡C-G²-, G² is

and n is 1. In still other subgroups, L¹ is —(CH₂), —C(H)═C(H)-G²-, G²is

and n is 1.

In compounds of formula (I), (Ia), or (II), R¹ is COOR¹⁰, CONR¹⁰R¹¹,CH₂OR¹⁰, SO₃R¹⁰, SO₂NR¹⁰R¹¹, PO(OR¹⁰)₂, or tetrazol-5-yl; wherein R¹⁰ isH, C₁-C₄ alkyl (e.g., methyl, ethyl) or aryl (e.g., phenyl) and R¹¹ isH, C₁-C₄ alkyl (e.g., methyl, ethyl), COR¹², OR¹⁰, or SO₂R¹²; whereinR¹² is C₁-C₄ alkyl (e.g., methyl, ethyl). In one group of compounds, R¹is COOH or COOCH₃. In another group of compounds, R¹ is COOH.

In compounds of formula (I) or (Ia), L⁴ is —C(R²)₂—C(R³)₂—,—C(R²)═C(R³)—, —C≡C—, or

wherein R² and R³ are each H, CH₃, fluoro, or chloro. In someembodiments, L⁴ is —C(R²)₂—C(R³)₂— and R² and R³ are each hydrogen. Inother embodiments, L⁴ is —C(R²)═C(R³)— and R² and R³ are eachindependently H, CH₃, fluoro or chloro. In some groups of compounds, L⁴is —C(R²)═C(R³)— and R² and R³ are hydrogen. In certain subgroups, L⁴ is

In other embodiments, L⁴ is —C≡C—. In yet other embodiments, L⁴ is

In compounds of formula (I) or (Ia), L² is —CH₂— or a bond. In someembodiments, L² is a bond.

In compounds of formula (I), (Ia), or (II), R⁴ and R⁵ are eachindependently H, F, CF₃, or C₁-C₄ alkyl (e.g., methyl, ethyl, etc.); orR⁴ and R⁵ together with the carbon to which they are attached form aC₃-C₅ cycloalkyl (e.g., cyclopropyl),

In some embodiments, R⁴ and R⁵ are each independently hydrogen or CH₃.In other embodiments R⁴ is C₁-C₄ alkyl (e.g., methyl, ethyl, etc.) andR⁵ is hydrogen. In yet other embodiments, R⁴ is hydrogen and R⁵ is C₁-C₄alkyl (e.g., methyl, ethyl, etc.). In still other embodiments, R⁴ and R⁵are fluoro. In some embodiments, R⁴ is methyl and R⁵ is hydrogen. Inother embodiments, R⁴ is hydrogen and R⁵ is methyl.

In the compounds of formula (I), (Ia), or (II), the stereochemistry ofthe hydroxyl group on the lower chain may be either α or β or a mixtureof α and β.

In some embodiments of the invention, R⁶ is aryl or heteroaryl, eachoptionally substituted as described herein. In some groups of compounds,R⁶ is aryl, optionally substituted as described herein. In some groupsof compounds, R⁶ is phenyl optionally substituted with halogen (e.g.,fluoro, chloro), C₁-C₃haloalkyl (e.g., CF₃), or—C₁-C₃alkylene-C₁-C₃alkoxy (e.g., CH₂OCH₃). In other embodiments of theinvention, R⁶ is C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, or C₃-C₁₀haloalkynyl, eachoptionally substituted as described herein. In other embodiments, R⁶ isC₃-C₁₀alkyl (e.g., propyl, butyl, pentyl, octyl, etc.). In some groupsof compounds, R⁶ is n-propyl, n-butyl, or n-pentyl. In a particularsubgroups of compounds, R⁶ is n-butyl. In other embodiments, R⁶ isC₃-C₁₀alkynyl (e.g., propynyl, butynyl, pentynyl, hexynyl, etc.). Insome groups of compounds, R⁶ is but-2-yn-1-yl, pent-2-yn-1-yl, orhex-2-yn-1-yl. In particular subgroups, R⁶ is pent-2-yn-1-yl.

In some embodiments, R⁶ is L³-R⁷, where L³ and R⁷ are as defined herein.In other embodiments, L³ is C₁-C₆alkylene, C₂-C₆alkenylene, orC₂-C₆alkynylene. The C₁-C₆alkylene, C₂-C₆alkenylene, and C₂-C₆alkynyleneare optionally substituted with 1, 2, 3, or 4 fluoro substituents. Infurther embodiments, L³ is C₁-C₆alkylene (e.g., propylene, butylene,pentylene, etc.), optionally substituted. In further embodiments, L³ isC₁-C₆alkylene, where the C₁-C₆alkylene is a straight chain alkylenegroup. For, example, in some groups of compounds, L³ is n-propylene,n-butylene, or n-pentylene. In still other embodiments, L³ isC₂-C₆alkenylene (e.g., propenylene, butenylene, etc.). In otherembodiments L³ is C₂-C₆alkynylene (e.g., propynylene, butynylene, etc.).In other embodiments, L³ is —CH₂—C≡C—

In still further embodiments L³ is —(CH₂)_(m)-G³-(CH₂)_(q)—,—(CH₂)_(m)-G⁴-(CH₂)_(q)—, or -G⁵-C≡C—; wherein m and q are eachindependently 0, 1, 2, or 3 and m+q=0, 1, 2, 3, or 4. In one embodiment,L³ is —(CH₂)_(m)-G³-(CH₂)_(q)— and m, q, and G³ are as defined herein.In another embodiment, L³ is —(CH₂)_(m)-G⁴-(CH₂)_(q)— and m, q, and G⁴are as defined herein. In one embodiment, G⁴ is

or each optionally substituted as described herein. In anotherembodiment, G⁴ is

each optionally substituted as described herein. In another embodiment,L³ is -G⁵-C≡C—, wherein G⁵ is as defined herein. In one embodiment, G⁵is

optionally substituted as described herein. In another embodiment, G⁵ is

each optionally substituted as described herein. In another embodiment,G⁵ is

optionally substituted as described herein.

In compounds of formula (I), (Ia), or (II), R⁷ is C₃-C₈cycloalkyl (e.g.,cyclopropyl, cyclopentyl, cyclohexyl), aryl (e.g., phenyl, naphthyl),heteroaryl (e.g., thienyl, furanyl), or heterocyclyl (e.g.,tetrahydrofuranyl); wherein R⁷ is optionally substituted as describedherein. In some embodiments, R⁷ is aryl, optionally substituted. Inother embodiments, R⁷ is phenyl, optionally substituted. In some groupsof compounds, R⁷ is phenyl.

In one aspect of the invention are compounds of formula (I), (Ia), or(II), wherein L¹-R¹ is C₃-C₇alkylene-R¹, wherein the C₃-C₇alkylene isoptionally substituted with 1, 2, 3, or 4 fluoro substituents; or L¹-R¹is —(CH₂)_(n)-G²-(CH₂), —R¹, —(CH₂)_(n)—C≡C-G²-R¹, or—(CH₂)_(n)—C(H)═C(H)-G²-R¹, wherein n is 1, 2, 3, 4, or 5, p is 0, 1, 2,or 3, and n+p=1, 2, 3, 4, 5, or 6; G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; R¹ is COOR¹⁰; and R¹⁰ is H orC₁-C₄ alkyl. In one embodiment of this aspect of the invention L¹-R¹ isn-hexylene-COOR¹⁰, —(CH₂)_(n)-G²-(CH₂)_(p)—COOR¹⁰,—(CH₂)_(n)—C≡C-G²-COOR¹⁰, or —(CH₂)_(n)—C(H)═C(H)-G²-COOR¹⁰; wherein nis 1, 2 or 3, p is 0 or 1; G² is

and R¹⁰ is H or CH₃.

In one embodiment of this aspect of the invention, L¹-R¹ isC₃-C₇alkylene-R¹ and the C₃-C₇alkylene is optionally substituted with1-4 fluoro substituents. In one group of compounds, for example, L¹-R¹is n-pentylene-COOR¹⁰, n-hexylene-COOR¹⁰, n-heptylene-COOR¹⁰, etc., andR¹⁰ is H or CH₃. In one embodiment, L¹-R¹ is n-hexylene-COOH orn-hexylene-COOCH₃.

In another embodiment of this aspect of the invention, L¹-R¹ is—(CH₂)_(n)-G²-(CH₂)_(p)—R¹; and G₂ is

In another embodiment, L¹-R¹ is —(CH₂)_(n)-G²-COOR¹⁰ (i.e., p is 0), G²is

n is 2 or 3, and R¹⁰ is H or CH₃. In one embodiment, L¹-R¹ is

In another embodiment, L¹-R¹ is

In another embodiment of this aspect of the invention L¹-R¹ is—(CH₂)_(n)-G²-(CH₂)_(p)—R¹ and G² is

In another embodiment, L¹-R¹ is —(CH₂)_(n)-G²-COOR¹⁰ (i.e., p is 0), G²is

n is 2 or 3; and R¹⁰ is H or CH₃. In still another embodiment, L¹-R¹ is

In yet another embodiment, L¹-R¹ is

In another embodiment, L¹-R¹ is —CH₂-G²-CH₂—COOR¹⁰, G² is

and R¹⁰ is H or CH₃. In another embodiment, L¹-R¹ is —CH₂-G²-CH₂—COOR¹⁰,G² is

and R⁹ is H.

In still another embodiment of this aspect of the invention, L¹-R¹ is—(CH₂)_(n)—C≡C-G²-COOR¹⁰ and G² is

In yet another embodiment, L¹-R¹ is —(CH₂)_(n)—C≡C-G²-COOR¹⁰, G² is

n is 1, and R¹⁰ is H or CH₃. In another embodiment, L¹-R¹ is—(CH₂)_(n)—C≡C-G²-COOR¹⁰, G² is

1, and R¹⁰ is H.

In another embodiment of this aspect of the invention, L¹-R¹ is—(CH₂)_(n)—C(H)═C(H)-G²-COOR¹⁰ and G² is

In another embodiment, L¹-R¹ is —(CH₂)_(n)—C(H)═C(H)-G²-COOR¹⁰, G² is

n is 1, and R¹⁰ is H or CH₃. In another embodiment, L¹-R¹ is—(CH₂)_(n)—C(H)═C(H)-G²-COOR¹⁰, G² is

n is 1, and R¹⁰ is H.

In another aspect of the invention are compounds of formula (I) or (Ia),wherein

(i.e., L² is a bond and s is 1), R⁶ is aryl, heteroaryl, C₃-C₁₀alkyl,C₃-C₁₀alkenyl, C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, orC₃-C₁₀haloalkynyl, (each optionally substituted as described herein) andL⁴, R⁴, and R⁵ are as defined herein. In a first embodiment of thisaspect of the invention, L⁴ is

and R⁴ and R⁵ are independently H or CH₃. In one group of compoundsaccording to the first embodiment, R⁶ is C₃-C₁₀ alkyl, C₃-C₁₀alkenyl,C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, or C₃-C₁₀haloalkynyl.In another group of compounds of this embodiment, R⁶ is C₃-C₁₀alkyl(e.g., propyl, butyl, pentyl, octyl, etc.). In a subgroup of compounds,R⁶ is n-propyl, n-butyl, or n-pentyl. In another subgroup, R⁶ isn-butyl. In another group of compounds of the first embodiment, R⁶ isC₃-C₁₀alkynyl (e.g., propynyl, butynyl, pentynyl, hexynyl, etc.). In asubgroup of compounds, R⁶ is but-2-yn-1-yl, pent-2-yn-1-yl, orhex-2-yn-1-yl. In another subgroup, R⁶ is pent-2-yn-1-yl. In anothergroup of compounds according to the first embodiment, R⁶ is aryl orheteroaryl, each optionally substituted as described herein. In onegroup of compounds, R⁶ is phenyl optionally substituted with halogen(e.g., fluoro, chloro), C₁-C₃haloalkyl (e.g., CF₃), or—C₁-C₃alkylene-C₁-C₃alkoxy (e.g., CH₂OCH₃). In a second embodiment ofthis aspect of the invention, L⁴ is —CH₂—CH₂— and R⁴ and R⁵ areindependently H or CH₃. In a third embodiment of this aspect of theinvention L⁴ is —C≡C— and R⁴ and R⁵ are independently H or CH₃. In afourth embodiment of this aspect of the invention, L⁴ is

and R⁴ and R⁵ are independently H or CH₃. Groups of compounds accordingto the second, third, and fourth embodiments include those where R⁶ isC₃-C₁₀alkyl (e.g., propyl, butyl, pentyl, octyl, etc.), C₃-C₁₀alkynyl(e.g., propynyl, butynyl, pentynyl, hexynyl, etc.), or phenyl optionallysubstituted with halogen (e.g., fluoro, chloro), C₁-C₃haloalkyl (e.g.,CF₃), or —C₁-C₃alkylene-C₁-C₃alkoxy (e.g., CH₂OCH₃).

In another aspect of the invention are compounds of formula (I) or (Ia),wherein

(i.e., L² is a bond, s is 1, and R⁴ and R⁵ are fluoro), R⁶ is aryl,heteroaryl, C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl,C₃-C₁₀haloalkenyl, or C₃-C₁₀haloalkynyl, (each optionally substituted asdescribed herein), and L⁴ is as defined herein. In a first embodimentaccording to this aspect of the invention, L⁴ is

and R⁶ is aryl, optionally substituted as describe herein. In one groupof compounds according to the first embodiment R⁶ is phenyl, optionallysubstituted. In another group of compounds R⁶ is C₃-C₁₀alkyl,C₃-C₁₀alkenyl, C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl,C₃-C₁₀haloalkynyl.

In another aspect of the invention are compounds of formula (I) or (Ia),wherein

(i.e., L² is a bond, s is 1, and R⁶ is L³-R⁷), L³ is C₁-C₆alkylene,C₂-C₆alkenylene, or C₂-C₆alkynylene (each optionally substituted with 1,2, 3, or 4 fluoro substituents), and L⁴, R⁴, R⁵, and R⁷ are as definedherein. In a first embodiment of this aspect of the invention, L⁴ is

R⁴ and R⁵ are independently H or CH₃. In one group of compoundsaccording to the first embodiment, R⁷ is C₃-C₈cycloalkyl (e.g.,cyclopropyl, cyclopentyl, cyclohexyl), aryl (e.g., phenyl, naphthyl),heteroaryl (e.g., thienyl, furanyl), or heterocyclyl (e.g.,tetrahydrofuranyl); wherein R⁷ is optionally substituted as describedherein. In one group of compounds of this embodiment, L³ isC₁-C₆alkylene (e.g., propylene, butylene, pentylene, etc.) and R⁷ isphenyl, naphthyl, thienyl, or cyclohexyl, each optionally substituted.In another group of compounds of this embodiment, L³ is C₁-C₆alkylene(e.g., propylene, butylene, pentylene, etc.), where the C₁-C₆alkylene isa straight chain alkylene group, and R⁷ is phenyl optionallysubstituted. In a subgroup of compounds L³ is n-propylene, n-butylene,or n-pentylene and R⁷ is phenyl. In another group of compounds of thisembodiment, L³ is C₂-C₆alkenylene (e.g., propenylene, butenylene, etc.)and R⁷ is phenyl, naphthyl, thienyl, or cyclohexyl, each optionallysubstituted. In another group of compounds of this embodiment, L³ isC₂-C₆alkynylene (e.g., propynylene, butynylene, etc.) and R⁷ is phenyl,naphthyl, thienyl, or cyclohexyl, each optionally substituted. In asubgroup of compounds, L³ is —CH₂—C≡C—, and R⁷ is phenyl. In a secondembodiment of this aspect of the invention, L⁴ is —CH₂—CH₂— and R⁴ andR⁵ are independently H or CH₃. In a third embodiment of this aspect ofthe invention L⁴ is —C≡C— and R⁴ and R⁵ are independently H or CH₃. In afourth embodiment of this aspect of the invention, L⁴ is

and R⁴ and R⁵ are independently H or CH₃. Groups of compounds accordingto the second, third, and fourth embodiments include those where L³ isC₂-C₆alkylene (e.g., propylene, butylene, pentylene, etc.),C₂-C₆alkenylene (e.g., propenylene, butenylene, etc.), orC₂-C₆alkynylene (e.g., propynyl, butynyl, etc.), and R⁷ is phenyl,naphthyl, thienyl, or cyclohexyl, each optionally substituted.

In another aspect of the invention,

L³ is —(CH₂)_(m)-G³-(CH₂)_(q)—, —(CH₂)_(m)-G⁴-(CH₂)_(q)—, or -G⁵-C≡C—;and L⁴, G³, G⁴, G⁵, R⁴, R⁵, R⁷, m, and q are as defined herein. In afirst embodiment of this aspect of the invention, L⁴ is

and R⁴ and R⁵ are independently H or CH₃. In one group of compoundsaccording to the first embodiment, L³ is -G⁵-C≡C—, G⁵ is

and R⁷ is C₃-C₈cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl),aryl (e.g., phenyl, naphthyl), heteroaryl (e.g., thienyl, furanyl), orheterocyclyl (e.g., tetrahydrofuranyl); wherein R⁷ is optionallysubstituted as described herein.

In another aspect of the invention,

L⁴ is —C(R²)═C(R³)—; R² and R³ are each hydrogen; R⁴ and R⁵ areindependently H or C₁-C₄ alkyl; R⁶ is C₃-C₁₀alkyl, C₃-C₁₀alkynyl, orL³-R⁷; L³ is C₁-C₆alkylene or C₂-C₆alkynylene; wherein the C₁-C₆alkyleneand C₂-C₆alkynylene are optionally substituted with 1, 2, 3, or 4 fluorosubstituents; and R⁷ is aryl, wherein R⁷ is optionally substituted with1, 2, 3, or 4 substituents selected from the group consisting ofC₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy.

In another aspect of the invention are compounds of formula (I) or (Ia),wherein:

L¹-R¹ is C₃-C₇alkylene-R¹, wherein the C₃-C₇alkylene is optionallysubstituted with 1, 2, 3, or 4 fluoro substituents; or L¹-R¹ is—(CH₂)_(n)-G²-(CH₂)_(p)—R¹, —(CH₂)_(n)—C≡C-G²-R¹, or—(CH₂)_(n)—C(H)═C(H)-G²-R¹, wherein n is 1, 2, 3, 4, or 5, p is 0, 1, 2,or 3, and n+p=1, 2, 3, 4, 5, or 6; G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; R¹ is COOR¹⁰; R¹⁰ is H orC₁-C₄ alkyl; and

L⁴ is —C(R²)₂—C(R³)₂—, —C(R²)═C(R³)—, —C≡C—, or

wherein R² and R³ are each H, CH₃, fluoro, or chloro; R⁴ and R⁵ are eachindependently H, F, CF₃, or C₁-C₄ alkyl; or R⁴ and R⁵ together with thecarbon to which they are attached form a C₃-C₅ cycloalkyl; R⁶ is aryl,C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl,C₃-C₁₀haloalkenyl, C₃-C₁₀haloalkynyl, or L³-R⁷; L³ is C₁-C₆alkylene,C₂-C₆alkenylene, or C₂-C₆alkynylene wherein the C₁-C₆alkylene,C₂-C₆alkenylene, and C₂-C₆alkynylene are optionally substituted with 1,2, 3, or 4 fluoro substituents; and R⁷ is aryl, wherein R⁷ is optionallysubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy.

In one embodiment according to the foregoing aspect of the invention, L⁴is

R⁴ and R⁵ are independently H or C₁-C₄ alkyl; R⁶ is C₃-C₁₀alkyl,C₃-C₁₀alkenyl, C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl,C₃-C₁₀haloalkynyl, or L³-R⁷; L³ is C₁-C₆alkylene, C₂-C₆alkenylene, orC₂-C₆alkynylene; wherein the C₁-C₆alkylene, C₂-C₆alkenylene, andC₂-C₆alkynylene are optionally substituted with 1, 2, 3, or 4 fluorosubstituents; and R⁷ is aryl, wherein R⁷ is optionally substituted with1, 2, 3, or 4 substituents selected from the group consisting ofC₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy.

In one group of compounds according to the foregoing embodiment, L¹-R¹is C₃-C₇alkylene-R¹; or L¹-R¹ is —(CH₂)_(n)-G²-(CH₂)_(p)—R¹,—(CH₂)_(n)—C≡C-G²-R¹, or —(CH₂)_(n)—C(H)═C(H)-G²-R¹, wherein n is 1, 2or 3, p is 0, 1, or 2, and n+p=1, 2, 3 or 4; G² is

R¹ is COOR¹⁰; R¹⁰ is H or C₁-C₄ alkyl; R⁴ and R⁵ are independently H orCH₃; L³ is ethynylene, propynylene, or butynylene; and R⁶ is phenyl orC₁-C₆alkyl, wherein the phenyl is optionally substituted with 1, 2, 3,or 4 substituents selected from the group consisting of C₁-C₄alkyl,C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy; and—C₁-C₃alkylene-C₁-C₃alkoxy.

In one group of compounds according to the foregoing embodiment, L¹-R¹is C₃-C₇alkylene-R¹; or L¹-R¹ is —(CH₂)_(n)-G²-(CH₂)_(p)—R¹, wherein nis 2 or 3 and p is 0; G² is

R¹ is COOR¹⁰; and R¹⁰ is H or C₁-C₄ alkyl.

In one group of compounds according to the foregoing embodiment, R⁴ andR⁵ are independently H or CH₃; R⁶ is C₃-C₁₀alkyl, C₃-C₁₀alkynyl, orL³-R⁷; L³ is C₁-C₆alkylene or C₂-C₆alkynylene; wherein the C₁-C₆alkyleneand C₂-C₆alkynylene are optionally substituted with 1, 2, 3, or 4 fluorosubstituents; and R⁷ is aryl, wherein R⁷ is optionally substituted with1, 2, 3, or 4 substituents selected from the group consisting ofC₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy. In one subgroup ofcompounds, L¹ is C₃-C₇alkylene or —(CH₂)_(n)-G²-(CH₂)_(p)—, wherein n is2 or 3 and p is 0; and G² is

In another subgroup of compounds, L¹ is C₃-C₇alkylene or —(CH₂)_(n)-G²-;n is 2 or 3; G² is

R⁶ is propyl, butyl, pentyl, propynyl, butynyl, pentynyl, hexynyl, orL³-R⁷; L³ is propylene, butylene, pentylene, propynylene, or butynylene;and R⁷ is phenyl or phenyl optionally substituted. In another subgroupof compounds, L¹ is C₃-C₇alkylene and R⁶ is propyl, butyl, pentyl,propynyl, butynyl, pentynyl, or hexynyl. In another subgroup ofcompounds, L¹ is C₃-C₇alkylene and R⁶ is L³-R⁷; L³ is propylene,butylene, pentylene, propynylene, or butynylene; and R⁷ is phenyl orphenyl optionally substituted. In another subgroup of compounds, L¹ is—(CH₂)_(n)-G²-, wherein n is 2 or 3; G² is

and R⁶ is propyl, butyl, pentyl, propynyl, butynyl, pentynyl, orhexynyl. In another subgroup of compounds, L¹ is —(CH₂)_(n)-G²-, whereinn is 2 or 3; G² is

and R⁶ is L³-R⁷; L³ is propylene, butylene, pentylene, propynylene, orbutynylene; and R⁷ is phenyl or phenyl optionally substituted. In afurther subgroup, L¹ is n-hexylene or —(CH₂)_(n)-G²-, wherein n is 2 or3; G² is

R is COOR¹⁰; R¹⁰ is H or CH₃; R⁶ is n-butyl, but-2-yn-1-yl,pent-2-yn-1-yl, hex-2-yn-1-yl, or L³-R⁷; L³ is n-propylene, n-butylene,or n-pentylene or —CH₂—C≡C—; and R⁷ is phenyl or phenyl optionallysubstituted. In another subgroup of compounds, L¹ is n-hexylene; R¹ isCOOR¹⁰; R¹⁰ is H or CH₃; and R⁶ is n-butyl, but-2-yn-1-yl,pent-2-yn-1-yl, or hex-2-yn-1-yl. In another subgroup of compounds, L¹is n-hexylene; R¹ is COOR¹⁰; R¹⁰ is H or CH₃; and R⁶ is L³-R⁷; L³ isn-propylene, n-butylene, n-pentylene or —CH₂—C≡C—; and R⁷ is phenyl orphenyl optionally substituted. In another subgroup of compounds, L¹ is—(CH₂)_(n)-G²-, wherein n is 2 or 3; G² is

R¹ is COOR¹⁰; R¹⁰ is H or CH₃; and R⁶ is n-butyl, but-2-yn-1-yl,pent-2-yn-1-yl or hex-2-yn-1-yl. In another subgroup of compounds, L¹ is—(CH₂)_(n)-G²-, wherein n is 2 or 3; G² is

R¹ is COOR¹⁰; R¹⁰ is H or CH₃; and R⁶ is L³-R⁷; L³ is n-propylene,n-butylene, n-pentylene or —CH₂—C≡C—; and R⁷ is phenyl or phenyloptionally substituted.

In another group of compounds according to the foregoing embodiment, R⁶is C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl,C₃-C₁₀haloalkenyl, or C₃-C₁₀haloalkynyl. In a subgroup of compounds, L¹is C₃-C₇alkylene, wherein the alkylene is optionally substituted with 1,2, 3, or 4 fluoro substituents. In a further subgroup, R⁶ isC₃-C₁₀alkyl, C₃-C₁₀alkenyl, or C₃-C₁₀alkynyl; and L¹ is C₃-C₇alkylene.In another subgroup, L¹ is —(CH₂)_(n)-G²-(CH₂)_(p)—, —(CH₂)_(n)—C≡C-G²-,or —(CH₂)_(n)—C(H)═C(H)-G²-, wherein n is 1, 2, 3, 4, or 5, p is 0, 1,2, or 3, and n+p=1, 2, 3, 4, 5, or 6; and G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy. In a further subgroup, R⁶ isC₃-C₁₀alkyl, C₃-C₁₀alkenyl, or C₃-C₁₀alkynyl; and L¹ is—(CH₂)_(n)-G²-(CH₂)_(p)—, wherein n is 2 or 3 and p is 0; and G² is

In yet another group of compounds according to the foregoing embodiment,R⁶ is L³-R⁷; L³ is C₁-C₆alkylene, C₂-C₆alkenylene, or C₂-C₆alkynylene;wherein the C₁-C₆alkylene, C₂-C₆alkenylene, and C₂-C₆alkynylene areoptionally substituted with 1, 2, 3, or 4 fluoro substituents; and R⁷ isaryl, wherein R⁷ is optionally substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₄alkyl,C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy, and—C₁-C₃alkylene-C₁-C₃alkoxy. In one subgroup of compounds, L¹ isC₃-C₇alkylene, wherein the C₃-C₇alkylene is optionally substituted with1, 2, 3, or 4 fluoro substituents. In a further subgroup of compounds,R⁶ is L³-R⁷; L³ is C₁-C₆alkylene, C₂-C₆alkenylene, or C₂-C₆alkynylene;R⁷ is aryl or optionally substituted aryl; and L¹ is C₃-C₇alkylene. Instill another subgroup R⁶ is L³-R⁷; L³ is C₁-C₆alkylene,C₂-C₆alkenylene, or C₂-C₆alkynylene; R⁷ is phenyl or phenyl optionallysubstituted; and L¹ is C₃-C₇alkylene. In another subgroup, L¹ is—(CH₂)_(n)-G²-(CH₂)_(p)—, —(CH₂)_(n)—C≡C-G²-, or—(CH₂)_(n)—C(H)═C(H)-G²-, wherein n is 1, 2, 3, 4, or 5, p is 0, 1, 2,or 3, and n+p=1, 2, 3, 4, 5, or 6; and G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy. In a further subgroup ofcompounds, R⁶ is L³-R⁷; L³ is C₁-C₆alkylene, C₂-C₆alkenylene, orC₂-C₆alkynylene; R⁷ is aryl; L¹ is —(CH₂)_(n)-G²-(CH₂)_(p)—, wherein nis 2 or 3, and p is 0; and G² is

In still another subgroup R⁶ is L³-R⁷; L³ is C₁-C₆alkylene,C₂-C₆alkenylene, or C₂-C₆alkynylene; R⁷ is phenyl or phenyl optionallysubstituted; and L¹ is —(CH₂)_(n)-G²-(CH₂)_(p)—, wherein n is 2 or 3,and p is 0; and G² is

In still another group of compounds according to the foregoingembodiment, L¹ is C₃-C₇alkylene, wherein the C₃-C₇alkylene is optionallysubstituted with 1, 2, 3, or 4 fluoro substituents.

In another group of compounds according to the foregoing embodiment, L¹is —(CH₂)_(n)-G²-(CH₂)_(p)—, —(CH₂)_(n)—C≡C-G²-, or—(CH₂)_(n)—(H)═C(H)-G²-, wherein n is 1, 2, 3, 4, or 5, p is 0, 1, 2, or3, and n+p=1, 2, 3, 4, 5, or 6; and G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy. In one subgroup of compounds,L¹ is —(CH₂)_(n)-G²-(CH₂)_(p)—, wherein n is 2 or 3, p is 0, and G² is

In another aspect of the invention are compounds of formula (II)

wherein:

L¹ is

a) C₃-C₇alkylene, C₃-C₇alkenylene, or C₃-C₇alkynylene, wherein theC₃-C₇alkylene, C₃-C₇alkenylene, or C₃-C₇alkynylene are each optionallysubstituted with 1, 2, 3, or 4 fluoro substituents;

b) —(CH₂)_(t)-G-(CH₂)_(p)—; wherein t is 0, 1, or 2, p is 0, 1, 2, or 3,and t+p=0, 1, 2, 3, or 4; or

c) —(CH₂)_(n)-G¹-(CH₂)_(p)—, —(CH₂)_(n)-G²-(CH₂)_(p)—,—(CH₂)_(n)—C≡C-G²-, or —(CH₂)_(n)—C(R¹³)═C(R³)-G²-, wherein n is 1, 2,3, 4, or 5, p is 0, 1, 2, or 3, and n+p=1, 2, 3, 4, 5, or 6;

G is,

G¹ is O, C(O), S, S(O), S(O)₂, or NR⁸; wherein R⁸ is H, C₁-C₄ alkyl, orC₁-C₄alkylcarbonyl;

G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy;

R¹ is COOR¹⁰, CONR¹⁰R¹¹, CH₂OR¹⁰, SO₃R¹⁰, SO₂NR¹⁰R¹¹, PO(OR¹⁰)₂, ortetrazol-5-yl;

R¹⁰ is H, C₁-C₄ alkyl, or aryl;

R¹¹ is H, C₁-C₄ alkyl, COR¹², OR¹⁰, or SO₂R¹²;

R¹² is C₁-C₄ alkyl;

R¹³, at each occurrence, is independently H or C₁-C₄alkyl;

R⁴ and R⁵ are each independently H, F, CF₃, or C₁-C₄ alkyl; or R⁴ and R⁵together with the carbon to which they are attached form a C₃-C₅cycloalkyl

R⁶ is aryl, heteroaryl, C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, C₃-C₁₀haloalkynyl, or L³-R⁷; whereinthe aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₄alkyl,C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy; and—C₁-C₃alkylene-C₁-C₃alkoxy; and wherein the C₃-C₁₀alkyl, C₃-C₁₀alkenyl,C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, and C₃-C₁₀haloalkynylare optionally substituted with a substituent selected from the groupconsisting of COOR¹⁰, CONR¹⁰R¹¹, CH₂OR¹⁰, SO₃R¹⁰, SO₂NR¹⁰R¹¹, PO(OR¹⁰)₂,and tetrazol-5-yl;

L³ is C₁-C₆alkylene, C₂-C₆alkenylene, C₂-C₆alkynylene,—(CH₂)_(m)-G³-(CH₂)_(q)—, —(CH₂)_(m)-G⁴-(CH₂)_(q)—, or -G⁵-C≡C—; whereinthe C₁-C₆alkylene, C₂-C₆alkenylene, and C₂-C₆alkynylene are optionallysubstituted with 1, 2, 3, or 4 fluoro substituents; and wherein m and qare each independently 0, 1, 2, or 3 and m+q=0, 1, 2, 3, or 4;

G³ is O, C(O), S, S(O), S(O)₂, or NR⁹; wherein R⁹ is H, C₁-C₄ alkyl, orC₁-C₄alkylcarbonyl;

G⁴ is

wherein G⁴ is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy;

G⁵ is

wherein G⁵ is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy;

R⁷ is C₃-C₈cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein R⁷ isoptionally substituted with 1, 2, 3, or 4 substituents selected from thegroup consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy; and

r is 0 or 1.

In one embodiment according to the foregoing aspect, L¹ isC₃-C₇alkylene, —(CH₂)_(n)-G²-(CH₂)_(p)—, —(CH₂)_(n)—C≡C-G²-, or—(CH₂)_(n)—C(H)═C(H)-G²-, wherein n is 1, 2, 3, 4, or 5, p is 0, 1, 2,or 3, and n+p=1, 2, 3, 4, 5, or 6; G² is

R¹ is COOR¹⁰; R¹⁰ is H or C₁-C₄ alkyl; R⁴ and R⁵ are each independentlyH or C₁-C₄ alkyl; R⁶ is C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl, orL³-R⁷; L³ is C₁-C₆alkylene, C₂-C₆alkynylene, or C₂-C₆alkynylene; and R⁷is aryl, optionally substituted as described herein.

In another embodiment according to the foregoing aspect, L¹ isC₃-C₇alkylene or —(CH₂)_(n)-G²-(CH₂)_(p)—, wherein n is 2, 3, 4, or 5, pis 0, 1, 2, or 3, and n+p=2, 3, 4, 5, or 6; G² is

R¹ is COOR¹⁰; R¹⁰ is H or C₁-C₄ alkyl; R⁴ and R⁵ are each independentlyH or C₁-C₄ alkyl; R⁶ is C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl, orL³-R⁷; L³ is C₁-C₆alkylene, C₂-C₆alkynylene, or C₂-C₆alkynylene; and R⁷is aryl, optionally substituted as described herein.

In another embodiment, L¹ is C₃-C₇alkylene or —(CH₂)_(n)-G²-(CH₂)_(p)—,wherein n is 2 or 3, p is 0; G² is

R¹ is COOR¹⁰; R¹⁰ is H or C₁-C₄ alkyl; R⁴ and R⁵ are each independentlyH or C₁-C₄ alkyl; R⁶ is C₃-C₁₀alkyl, C₃-C₁₀alkynyl, or L³-R⁷; L³ isC₁-C₆alkylene, C₂-C₆alkynylene, or C₂-C₆alkynylene; and R⁷ is aryl,optionally substituted as described herein.

In another aspect, the invention provides a compound selected from thegroup consisting of:

-   methyl    7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    7-((5R)-3,3-difluoro-5-((E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    7-((5R)-3,3-difluoro-5-((E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((R)-3,3-difluoro-5-((R,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((R,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   methyl    4-(2-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;-   methyl    4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;-   methyl    4-(2-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;-   methyl    4-(2-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;-   4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxydec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   methyl    4-(2-((5R)-3,3-difluoro-5-((E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;-   methyl    4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;-   methyl    4-(2-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;-   4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxydec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((5R)-3,3-difluoro-5-((E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((S)-3,3-difluoro-5-((S)-3-hydroxy-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((S)-3,3-difluoro-5-((S)-3-hydroxy-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)heptanoate;-   methyl    7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)heptanoate;-   7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   (R)-1-(6-(1H-tetrazol-5-yl)hexyl)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)pyrrolidin-2-one;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)-N-ethylheptanamide;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)-N-(methylsulfonyl)heptanamide;-   7-((S)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,Z)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   3-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)benzoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)hept-5-ynoic    acid;-   (Z)-7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)hept-5-enoic    acid;-   5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)prop-1-yn-1-yl)thiophene-2-carboxylic    acid;-   4-((2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)thio)butanoic    acid;-   7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic    acid;-   4-(2-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)ethyl)benzoic    acid;-   3-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)benzoic    acid;-   4-((2-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)ethyl)thio)butanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S)-3-hydroxy-4-methyl-7-phenylhept-1-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-5-((3S,4S,E)-7-cyclohexyl-3-hydroxy-4-methylhept-1-en-1-yl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-(naphthalen-2-yl)hept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-(naphthalen-1-yl)hept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-7-(3-fluorophenyl)-3-hydroxy-4-methylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-(m-tolyl)hept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-5-((3S,4S,E)-7-(3-chlorophenyl)-3-hydroxy-4-methylhept-1-en-1-yl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-7-(3-methoxyphenyl)-4-methylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-7-(3-(methoxymethyl)phenyl)-4-methylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-6-(phenylthio)hex-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-6-phenoxyhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-5-((3S,4S,E)-4-ethyl-3-hydroxy-7-phenylhept-1-en-1-yl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-isopropyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-7-phenyl-4-(trifluoromethyl)hept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-5-((R,E)-4,4-difluoro-3-hydroxy-7-phenylhept-1-en-1-yl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-3,3-difluoro-5-((R,E)-3-hydroxy-4-methylene-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid;-   7-((R)-5-((R,E)-4-(difluoromethylene)-3-hydroxy-7-phenylhept-1-en-1-yl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoic    acid; and-   7-((R)-3,3-difluoro-5-((R,E)-3-hydroxy-3-(1-(3-phenylpropyl)cyclobutyl)prop-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoic    acid; or

a pharmaceutically acceptable salt thereof.

Compounds described herein may exist as stereoisomers wherein asymmetricor chiral centers are present. These stereoisomers are “R” or “S”depending on the configuration of substituents around the chiral carbonatom. The terms “R” and “S” used herein are configurations as defined inIUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry,Pure Appl. Chem., 1976, 45: 13-30.

The various stereoisomers (including enantiomers and diastereomers) andmixtures thereof of the compounds described are also contemplated.Individual stereoisomers of compounds described may be preparedsynthetically from commercially available starting materials thatcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution of the individual stereoisomer usingmethods that are known to those of ordinary skill in the art. Examplesof resolution are, for example, (i) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography, followed byliberation of the optically pure product; or (ii) separation of themixture of enantiomers or diastereomers on chiral chromatographiccolumns.

Geometric isomers may exist in the present compounds. All variousgeometric isomers and mixtures thereof resulting from the disposition ofsubstituents around a carbon-carbon double bond, a carbon-nitrogendouble bond, a cycloalkyl group, or a heterocycle group arecontemplated. Substituents around a carbon-carbon double bond or acarbon-nitrogen bond are designated as being of Z or E configuration andsubstituents around a cycloalkyl or a heterocycle are designated asbeing of cis or trans configuration.

It is to be understood that compounds disclosed herein may exhibit thephenomenon of tautomerism.

Thus, the formulae within this specification can represent only one ofthe possible tautomeric forms. It is to be understood that encompassedherein are any tautomeric form, and mixtures thereof, and is not to belimited merely to any one tautomeric form utilized within the naming ofthe compounds or formulae.

Additionally, unless otherwise stated, the structures depicted hereinare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structures except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C— or¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools, probes in abiological assay, or as EP₄ receptor agonists.

Also contemplated as part of the invention are compounds formed bysynthetic means or formed in vivo by biotransformation or by chemicalmeans. For example, certain compounds of the invention may function asprodrugs that are converted to other compounds of the invention uponadministration to a subject.

Methods of Treatment

The compounds of the invention are EP₄ receptor agonists and are usefulin treating or preventing conditions or diseases responsive to an EP₄receptor agonist. Conditions or diseases treatable with compounds of theinvention include elevated intraocular pressure, glaucoma, ocularhypertension, dry eye, macular edema, macular degeneration, alopecia(alone or in combination with, for example, an L-PGDS inhibitor or anH-PGDS inhibitor or in combination with both an L-PGDS inhibitor andH-PGDS inhibitor; Garza, L. A. et al, Science Translational Medicine,2012, 4(126), 126ra34), cerebralvascular accident (Liang, X. et al,Journal of Clinical Investigation, 2011, 121(11), 4362-4371), braindamage due to trauma, neuropathic pain (e.g., diabetic neuropathy,sciatica, post-herpetic neuralgia, HIV-related neuropathy, trigeminalneuralgia, ductus arteriosis, chemotherapy-induced pain), low bonedensity due to osteoporosis (Cameron, K. O. et al, Bioorganic andMedicinal Chemistry Letters, 2006, 16, 1799-1802) or glucocorticoidtreatment, bone fracture, and bone loss due to periodontal disease,surgical procedures, cancer, or trauma. Further uses of the compounds ofthe invention include use in increasing bone density in preparation ofbone for receiving dental or orthopedic implants, coating of implantsfor enhanced osseointegration, and use in all forms of spinal fusion.

The present invention provides methods of treatment comprisingadministering to a patient in need thereof: (i) a therapeuticallyeffective amount of a compound of formula (I), (Ia), or (II) or apharmaceutically acceptable salt thereof, or a solvate of either; or(ii) a composition comprising any of the foregoing compound, salt, orsolvate and a pharmaceutically acceptable carrier.

In one aspect, the invention provides a method of treating glaucoma,osteoporosis, bone fracture, low bone density due to periodontaldisease, or neuropathic pain.

In another aspect, the invention provides a method of stimulating boneformation. According to this aspect of the invention, one embodimentprovides a method of treating osteoporosis, bone fracture, andperiodontal disease. In another embodiment, the compound or compositionof the invention is administered alone. In still another embodiment, thecompound or composition is administered in combination with one or moreadditional therapeutic agents to treat bone loss or osteoporosis.Compounds of the invention can be used in combination with other agentsuseful in treating or preventing bone loss such as an organicbisphosphonate (e.g., alendronic acid or sodium alendronate); acathepsin K inhibitor; an estrogen or an estrogen receptor modulator;calcitonin; an inhibitor of osteoclast proton ATPase; an inhibitor ofHMG-CoA reductase; an integrin receptor antagonist; a RANKL inhibitorsuch as denosumab; a bone anabolic agent, such as PTH; a bonemorphogenetic agent such as BMP-2, BMP-4, and BMP-7; Vitamin D or asynthetic Vitamin D analogue such as ED-70; an androgen or an androgenreceptor modulator, a SOST inhibitor; and the pharmaceuticallyacceptable salts and mixtures thereof. A preferred combination is acompound of the present invention and an organic bisphosphonate.

In another aspect, the invention provides a method of loweringintraocular pressure. According to this aspect of the invention, oneembodiment provides a method of treating glaucoma. In anotherembodiment, the compound or composition of the invention is administeredalone. In still another embodiment, the compound or composition isadministered in combination with one or more additional therapeuticagents that lower intraocular pressure such as a j-adrenergic blockingagent such as timolol, betaxolol, levobetaxolol, carteolol, levobunolol,a parasympathomimetic agent such as pilocarpine, a sympathomimeticagents such as epinephrine, iopidine, brimonidine, clonidine, orpara-aminoclonidine, a carbonic anhydrase inhibitor such as dorzolamide,acetazolamide, metazolamide or brinzolamide; and a prostaglandin such aslatanoprost, travaprost, or unoprostone, and the pharmaceuticallyacceptable salts and mixtures thereof.

In still another aspect, the invention provides a method of treatingneuropathic pain. According to this aspect of the invention, oneembodiment provides a method of treating diabetic neuropathy, sciatica,post-herpetic neuralgia, HIV-related neuropathy, trigeminal neuralgia,or chemotherapy-induced pain. In another embodiment, the compound orcomposition of the invention is administered alone. In still anotherembodiment, the compound or composition is administered in combinationwith one or more additional therapeutic agents that treat neuropathicpain such as gabapentin, pregabalin, duloxetine, and lamotrigine, andthe pharmaceutically acceptable salts and mixtures thereof.

Compounds described herein can be administered as a pharmaceuticalcomposition comprising the compounds of interest in combination with oneor more pharmaceutically acceptable carriers. The phrase“therapeutically effective amount” of the present compounds meanssufficient amounts of the compounds to treat disorders, at a reasonablebenefit/risk ratio applicable to any medical treatment. It isunderstood, however, that the total daily dosage of the compounds andcompositions can be decided by the attending physician within the scopeof sound medical judgment. The specific therapeutically effective doselevel for any particular patient can depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health and prior medicalhistory, sex and diet of the patient; the time of administration, routeof administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed; and like factorswell-known in the medical arts. For example, it is well within the skillof the art to start doses of the compound at levels lower than requiredto achieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved. Actual dosage levels ofactive ingredients in the pharmaceutical compositions can be varied soas to obtain an amount of the active compound(s) that is effective toachieve the desired therapeutic response for a particular patient and aparticular mode of administration. In the treatment of certain medicalconditions, repeated or chronic administration of compounds can berequired to achieve the desired therapeutic response. “Repeated orchronic administration” refers to the administration of compounds daily(i.e., every day) or intermittently (i.e., not every day) over a periodof days, weeks, months, or longer. In particular, the treatment ofchronic painful conditions may require such repeated or chronicadministration of the compounds. Compounds described herein may becomemore effective upon repeated or chronic administration such that thetherapeutically effective doses on repeated or chronic administrationcan be lower than the therapeutically effective dose from a singleadministration.

Combination therapy includes administration of a single pharmaceuticaldosage formulation containing one or more of the compounds describedherein and one or more additional pharmaceutical agents, as well asadministration of the compounds and each additional pharmaceuticalagent, in its own separate pharmaceutical dosage formulation. Forexample, a compound described herein and one or more additionalpharmaceutical agents, can be administered to the patient together, in asingle oral dosage composition having a fixed ratio of each activeingredient, such as a tablet or capsule; or each agent can beadministered in separate oral dosage formulations. Where separate dosageformulations are used, the present compounds and one or more additionalpharmaceutical agents can be administered at essentially the same time(e.g., concurrently) or at separately staggered times (e.g.,sequentially).

In one aspect of the invention, compounds of the invention, or apharmaceutically acceptable salt thereof, or a solvate of either; or(ii) a composition comprising any of the foregoing compound, salt, orsolvate and a pharmaceutically acceptable carrier are administered asthe active pharmaceutical agent. In another aspect, compounds of theinvention or a pharmaceutically acceptable salt thereof, or a solvate ofeither; or (ii) a composition comprising any of the foregoing compound,salt, or solvate and a pharmaceutically acceptable carrier areadministered to a subject and the administered compounds are convertedto the active pharmaceutical agent in the subject by chemical orbiotransformation.

Ophthalmic formulations of compounds of the invention may contain from0.001 to 5% and especially 0.001 to 0.1% of active agent. Higher dosagesas, for example, up to about 10% or lower dosages can be employedprovided the dose is effective in reducing intraocular pressure,treating glaucoma, increasing blood flow velocity or oxygen tension. Fora single dose, from between 0.001 to 5.0 mg, preferably 0.005 to 2.0 mg,and especially 0.005 to 1.0 mg of the compound can be applied to thehuman eye.

Compounds may be administered orally once or several times per day eachin an amount of from 0.001 mg to 100 mg per adult, preferably about 0.01to about 10 mg per adult. Compounds may also be administeredparenterally once or several times per day each in an amount of from 0.1ng to 10 mg per adult or continuously administered into a vein for 1hour to 24 hours per day. Compounds may also be administered locally tostimulate bone formation in an amount from 0.0001 μg to 500 μg.

Pharmaceutical Compositions

Pharmaceutical compositions comprise compounds described herein,pharmaceutically acceptable salts thereof, or solvates of either. Thepharmaceutical compositions comprising the compound, salt, or solvatedescribed herein can be formulated together with one or more non-toxicpharmaceutically acceptable carriers, either alone or in combinationwith one or more other medicaments as described hereinabove.

Pharmaceutical compositions of the present invention may be manufacturedby processes well known in the art, e.g., by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions can be administered to humans, othermammals, and birds orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointmentsor drops), bucally or as an oral or nasal spray. The term “parenterally”as used herein, refers to modes of administration which includeintravenous, intramuscular, intraperitoneal, intrasternal, subcutaneousand intraarticular injection and infusion.

The pharmaceutical compositions can further be administered to humans,other mammals, and birds locally to the desired site of action; forexample, into a bone void such as a tooth socket defect, adjacent to analveolar bone, or a bone defect caused by surgery, trauma, or disease.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol and the like), vegetableoils (such as olive oil), injectable organic esters (such as ethyloleate) and suitable mixtures thereof. Proper fluidity can bemaintained, for example, by the use of coating materials such aslecithin, by the maintenance of the required particle size in the caseof dispersions and by the use of surfactants.

These compositions can also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It can also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, can depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, cement, putty, and granules. In such solid dosage forms,the active compound can be mixed with at least one inert,pharmaceutically acceptable excipient or carrier, such as sodium citrateor dicalcium phosphate and/or a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form canalso comprise buffering agents.

Solid compositions of a similar type can also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theycan optionally contain opacifying agents and can also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms can containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, can contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, poly(lactic-co-glycolic acid),microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, tragacanth, collagen sponge, demineralized bone matrix, andmixtures thereof.

The compounds can also be administered in the form of liposomes. As isknown in the art, liposomes are generally derived from phospholipids orother lipid substances. Liposomes are formed by mono- or multi-lamellarhydrated liquid crystals which are dispersed in an aqueous medium. Anynon-toxic, physiologically acceptable and metabolizable lipid capable offorming liposomes can be used. The present compositions in liposome formcan contain, in addition to compounds described herein, stabilizers,preservatives, excipients and the like. The preferred lipids are naturaland synthetic phospholipids and phosphatidyl cholines (lecithins) usedseparately or together. Methods to form liposomes are known in the art.See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV,Academic Press, New York, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of compounds described hereininclude powders, sprays, ointments and inhalants. The active compoundscan be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which canbe required. Ophthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope.

The compounds can be used in the form of pharmaceutically acceptablesalts derived from inorganic or organic acids. The phrase“pharmaceutically acceptable salt” means those salts which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like and are commensurate with areasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq). The saltscan be prepared in situ during the final isolation and purification ofthe compounds or separately by reacting a free base function with asuitable organic acid. Representative acid addition salts include, butare not limited to acetate, adipate, alginate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, malate,maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as, but not limited to, methyl, ethyl, propyl,and butyl chlorides, bromides and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides suchas, but not limited to, decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; arylalkyl halides like benzyl and phenethylbromides and others. Water or oil-soluble or dispersible products arethereby obtained. Examples of acids which can be employed to formpharmaceutically acceptable acid addition salts include such inorganicacids as hydrochloric acid, hydrobromic acid, sulfuric acid, andphosphoric acid and such organic acids as acetic acid, fumaric acid,maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citricacid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds by reacting a carboxylic acid-containingmoiety with a suitable base such as, but not limited to, the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as, but notlimited to, lithium, sodium, potassium, calcium, magnesium and aluminumsalts and the like and nontoxic quaternary ammonia and amine cationsincluding ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,ethylamine and the like. Other representative organic amines useful forthe formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

Compounds described herein can exist in unsolvated as well as solvatedforms, including hydrated forms, such as hemi-hydrates. In general, thesolvated forms, with pharmaceutically acceptable solvents such as waterand ethanol, among others, are equivalent to the unsolvated forms.

Chemistry and Examples

Unless otherwise defined herein, scientific and technical terms used inconnection with the exemplary embodiments shall have the meanings thatare commonly understood by those of ordinary skill in the art.

Further, unless otherwise required by context, singular terms shallinclude pluralities and plural terms shall include the singular.Generally, nomenclature used in connection with, and techniques ofchemistry and molecular biology described herein are those well-knownand commonly used in the art.

It will be appreciated that the synthetic schemes and specific examplesare illustrative and are not to be read as limiting the scope of theinvention. Optimum reaction conditions and reaction times for eachindividual step may vary depending on the particular reactants employedand substituents present in the reactants used. Unless otherwisespecified, solvents, temperatures and other reaction conditions may bereadily selected by one of ordinary skill in the art. The skilledartisan will also appreciate that not all of the substituents in thecompounds of formula (I) will tolerate certain reaction conditionsemployed to synthesize the compounds. Routine experimentation, includingappropriate manipulation of the reaction conditions, reagents andsequence of the synthetic route, protection and deprotection may berequired in the case of particular compounds. Suitable protecting groupsand the methods for protecting and deprotecting different substituentsusing such suitable protecting groups are well known to those skilled inthe art; examples of which may be found in T. Greene and P. Wuts,Protecting Groups in Chemical Synthesis (3 d ed.), John Wiley & Sons, NY(1999), which is incorporated herein by reference in its entirety.

Furthermore, the skilled artisan will appreciate that in some cases, theorder in which moieties are introduced may vary. The particular order ofsteps required to produce the compounds of formula (I) is dependent uponthe particular compounds being synthesized, the starting compound, andthe relative stability of the substituted moieties. Thus, synthesis ofthe present compounds may be accomplished by methods analogous to thosedescribed in the synthetic schemes described herein and in the specificexamples, with routine experimentation (e.g., manipulation of thereaction conditions, reagents, and sequence of the synthetic steps).

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound is required, it may beobtained by carrying out one of the procedures described herein using anoptically active starting material (prepared, for example, by asymmetricinduction of a suitable reaction step), or by resolution of a mixture ofthe stereoisomers of the compound or intermediates using a standardprocedure (such as chromatographic separation, recrystallization orenzymatic resolution).

Similarly, when a pure geometric isomer of a compound is required, itmay be obtained by carrying out one of the above procedures using a puregeometric isomer as a starting material, or by resolution of a mixtureof the geometric isomers of the compound or intermediates using astandard procedure such as chromatographic separation.

Systematic names of compound structures have been generated by theConvert-Structure-to-Name function of Chem & Bio Draw 12.0 Ultra byCambridgeSoft®, which uses the Cahn-Ingold-Prelog rules forstereochemistry. When discussing individual atomic positions of compoundstructures, an alternative continuous numbering scheme for the lactamsas described below may be used.

Liquid chromatography-mass spectra (LC/MS) were obtained using anAgilent LC/MSD G1946D or an Agilent 1100 Series LC/MSD Trap G1311A orG2435A. Quantifications were obtained on a Cary 50 Bio UV-visiblespectrophotometer.

¹H, ¹³C, and ¹⁹F Nuclear magnetic resonance (NMR) spectra were obtainedusing a Varian INOVA nuclear magnetic resonance spectrometer at 400,100, and 376 MHz, respectively.

High performance liquid chromatography (HPLC) analytical separationswere performed on an Agilent 1100 or Agilent 1200 HPLC analytical systemand followed by an Agilent Technologies G1315B Diode Array Detector setat or near the UV_(max)@260 nm.

High performance liquid chromatography (HPLC) preparatory separationswere performed on a Gilson preparative HPLC system or an Agilent 1100preparative HPLC system and followed by an Agilent Technologies G1315BDiode Array Detector set at or near the UV_(max) @260 nm.

Analytical chiral HPLC separations were performed on an Agilent 1100analytical system and followed by an Agilent Technologies G1315B DiodeArray Detector set at or near the UV_(max) @260 nm.

Thin layer chromatography (TLC) analyses were performed on Uniplate™ 250μsilica gel plates (Analtech, Inc. Catalog No. 02521) and were typicallydeveloped for visualization using 50 volume % concentrated sulfuric acidin water spray unless otherwise indicated.

When used in the present application, the following abbreviations havethe meaning set out below:

Ac is acetyl;

ACN is acetonitrile;

BBr₃ is boron tribromide;

Bn is benzyl;

BnNH₂ is benzylamine;

BSA is bovine serum albumin;

CH₂Cl₂ is dichloromethane;

CHCl₃ is chloroform;

CDCl₃ is deuterochloroform;

CSA is camphorsulfonic acid;

DCC is N,N′-dicyclohexylcarbodiimide;

DME is 1,2-dimethoxyethane;

DMF is N,N-dimethylformamide;

DMP is 2,2-dimethoxypropane (also called, acetone dimethyl acetal);

DMSO is dimethyl sulfoxide;

DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene;

DIA is diisopropylamine;

DMAP is 4-dimethylaminopyridine;

EDC/EDAC is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride;

EDTA is ethylenediaminetetraacetic acid;

EE is ethoxyeth-1-yl;

ee is enantiomeric excess;

EIA is enzyme immunoassay;

Et is ethyl;

EtOAc is ethyl acetate;

EtOH is ethanol;

Et₃N is triethylamine;

HCl is hydrogen chloride;

HOBt is 1-hydroxybenzotriazole;

Me is methyl;

MeOH is methanol;

MTBE is methyl tert-butyl ether,

NaOMe is sodium methoxide;

nBuLi or n-BuLi is n-butyllithium;

NFSi is N-fluorobenzenesulfonimide;

NHS is N-hydroxysuccinimide;

NMP is 1-methyl-2-pyrrolidinone;

PG is a protecting group;

Ph is phenyl;

Pd(PPh₃)₄ is tetrakis(triphenylphosphine)palladium;

PhMe is toluene;

rt is room temperature;

TBAF is tetrabutylammonium fluoride;

TBS or TBDMS is tert-butyldimethylsilyl;

tBu or t-Bu is tert-butyl;

TEA is triethylamine;

TFA is trifluoroacetic acid;

THF is tetrahydrofuran;

TMS is trimethylsilyl; and

Tris-HCl is 2-amino-2-(hydroxymethyl)-1,3-propanediol hydrochloride.

The γ-lactam scaffold common to the compounds of the present inventionmay be derived from the difluorooxopyrrolidinyl intermediate,(R)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one ((R)-8), which may beprepared from commercially available(R)-(+)-5-oxopyrrolidine-2-carboxylic acid (D-pyroglutamic acid) (1) asillustrated in Scheme 1

D-pyroglutamic acid (1) may undergo acid-catalyzed esterification in analcohol solvent, such as methanol, as illustrated in Step A. Theresulting ester intermediate (2) may be reduced with sodium borohydridein a solvent, such as THF, to the alcohol intermediate(R)-5-(hydroxymethyl)pyrrolidin-2-one (3) as shown for Step B. Thefollowings Steps C, D, E, F, and G may be carried out according to theprocedures described in US 2009/0275537. Simultaneous protection of thealcohol and amide groups of intermediate 3 by the acid-catalyzedaddition of 2,2-dimethoxypropane (Step C) provides protectedintermediate 4. Subsequent repeat stepwise deprotonation followed byaddition of electrophilic fluorine using NFSi (Steps D and E) affordsthe α,α-difluoropyrrolidone intermediate 6. Treatment of intermediate 6with HCl in 1,4-dioxane and methanol (Step F) removes the protectinggroup and opens the lactam ring to provide intermediate 7. Annulation(Step G) is achieved with the use of a base, such as triethylamine, toprovide (R)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one ((R)-8).

An alternative preparation of (R)-8 is illustrated in Scheme 1A.

Intermediate (R)-3,3-dimethyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one(4) may be converted directly to its difluoro analog(R)-6,6-difluoro-3,3-dimethyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one(6) in a one-pot method (Step A) comprising the addition of a solutioncomprising sec-butyllithium in (about 1.1 molar equivalents ofsec-butyllithium) to a solution comprising 4 (limiting reagent) in THFat −78° C., stirring for about an hour at −78° C., subsequent additionof a solution comprising NFSi (about 1.1 molar equivalents of NFSi),stirring for about another hour at −78° C., addition of a solutioncomprising LiHMDS (about 1.1 molar equivalents), stirring for aboutanother hour at −78° C., subsequent addition of a solution comprisingNFSi (about 1.1 molar equivalents of NFSi), stirring for about anotherhour at −78° C., addition of a solution comprising LiHMDS (about 0.4molar equivalent), and stirring for about 30 minutes. Intermediate 5 maysubsequently be converted directly to (R)-8 by treatment (Step B) with astrongly acid gel-type ion-exchange resin.

Compounds of the present invention may be prepared from 8 or O-protected8 by general routes illustrated in Scheme 2.

Compounds of the present invention, (I), may be prepared from 8 orprotected 8, for example, by a process that comprises first installingthe upper chain with a nitrogen-carbon bond forming reaction (using 8 oran O-protected 8), wherein the nitrogen atom of the γ-lactam ring of 8forms a covalent bond with the appropriate upper chain carbon atom toprovide the corresponding 8+upper chain intermediate shown in Scheme 2.In some aspects of the present invention, the nitrogen-carbon formingreaction comprises an allylation reaction between 8 or anoxygen-protected analog of 8 and an alkylating agent comprising theupper chain moiety and a leaving group as illustrated in Scheme 2A. Insome aspects of the present invention, the alkylating agent is an alkylhalide such as an alkyl iodide, alkyl bromide, or alkyl triflate. Inother aspects of the present invention, the alkylating agent is an allylbromide. In other aspects of the present invention, the alkylating agentis a propargyl halide such as a propargyl bromide.

The installation of the upper chain may be followed by a process thatcomprises installation of the lower chain by way of a carbon-carbon bondforming reaction, wherein the hydroxymethyl group carbon atom attachedto the γ-position of the lactam ring of intermediate 8+upper chain formsa covalent bond (carbon-carbon single, double, or triple bond) with theappropriate lower chain carbon atom to provide the correspondingcompound (I). In some aspects of the present invention, the intermediate8+upper chain (directly from the alkylation reaction or its O-protectedanalog having undergone subsequent deprotection) is oxidized to thecorresponding aldehyde intermediate, which may be subsequently subjectedto Horner-Wadsworth-Emmons reaction conditions in the presence of aβ-keto phosphonate ester coupling partner to, after subsequent reductionof the resulting ketone to the corresponding alcohol, provide compounds(I) of the present invention, wherein L⁴ is a carbon-carbon double bond,as illustrated in Scheme 1B.

Alternatively, compounds of the present invention, (I), may be preparedfrom 8 or protected 8, for example, by a process that comprises firstinstalling the lower chain with a carbon-carbon bond forming reaction(using 8 or an N-protected 8), wherein the hydroxymethyl group carbonatom attached to the γ-position of the lactam ring of intermediate 8forms a covalent bond (carbon-carbon single, double, or triple bond)with the appropriate lower chain carbon atom to provide thecorresponding 8+lower chain intermediate shown in Scheme 2. Theinstallation of the lower chain may be followed by a process thatcomprises installation of the upper chain by way of nitrogen-carbon bondforming reaction, wherein the nitrogen atom of the γ-lactam ring of8+lower chain forms a covalent bond with the appropriate upper chaincarbon atom to provide the corresponding compound (I).

In some aspects of the present invention, the synthetic route to acompound (I) comprises a process wherein certain intermediates 8+upperchain may undergo chemical reaction or a series of chemical reactions,which are known in the art or disclosed herein, that chemically modifythe upper chain such that chemical installation and/or modification ofthe lower chain is facilitated.

In further aspects of the present invention, the synthetic route to acompound (I) comprises a process wherein a certain intermediate 8+upperchain may undergo chemical reaction or a series of chemical reactions,which are known in the art or disclosed herein, that chemically modifythe upper chain such that at least one particular functional group orother structural feature not incorporated into said intermediate isincorporated into the structure of invention compound (I).

In some aspects of the present invention, the synthetic route to acompound (I) comprises a process wherein certain intermediates 8+lowerchain may undergo chemical reaction or a series of chemical reactions,which are known in the art or disclosed herein, that chemically modifythe lower chain such that chemical installation and/or modification ofthe upper chain is facilitated.

In further aspects of the present invention, the synthetic route to acompound (I) comprises a process wherein a certain intermediate 8+lowerchain may undergo chemical reaction or a series of chemical reactions,which are known in the art or disclosed herein, that chemically modifythe lower chain such that at least one particular functional group orother structural feature not incorporated into said intermediate isincorporated into the structure of invention compound (I). For someembodiments of compound (I) wherein L⁴ is a carbon-carbon single bond,the synthesis may comprise a sequence of steps as shown in Scheme 2C.

Omission of the hydrogenation step of Scheme 2C may provide compounds ofFormula (I) wherein L⁴ is a carbon-carbon double bond and whereinvarious R⁴ and R⁵ may be incorporated. In some aspects, R⁴ and R⁵ aredetermined by the starting ketone used in the chemical route sequence.Some ketones that may be utilized for this purpose and are commerciallyavailable include butan-2-one, pentan-2-one, 3-methyl-2-butanone(Aldrich), cyclopropyl methyl ketone (Aldrich), cyclobutyl methyl ketone(Aldrich), and 1-cyclopentyl-ethanone (Aldrich). Starting ketones andsubstituted acetylenes may also be available according to publishedprocedures or methods well known to those skilled in the art.

Synthetic routes utilized to prepare compounds of the present inventiontypically proceed through a carbon-carbon double bond formation(olefination) step to install the compound's lower chain. Theolefination may be accomplished by the interaction of an appropriatealdehyde intermediate with an appropriate nucleophilic carbanionspecies. Such methods may include Wittig reactions, wherein thenucleophilic carbanion species is an appropriate organic phosphoniumylide. Another carbon-carbon bond forming reaction that may be employedis a Horner-Wadsworth-Emmons reaction, wherein the coupling partner withthe aldehyde is an appropriate organic phosphonate carbanion. Publishedreviews describing the general scope and mechanism along with variousprotocols for these types of olefination reactions include thefollowing:

-   Boutagy, J. and Thomas, R. Chemical Reviews, 1974, 74, 87-99.-   Wadsworth, W. S., Jr. Organic Reactions, 1977, 25, 73-253.-   Walker, B. J. in Organophosphorous Reagents in Organic Synthesis,    Cadogan, J. I. G., Ed.; Academic Press: New York, 1979, pp. 155-205.-   Schlosser, M. et al., Phosphorous and Sulfur and the Related    Elements, 1983, 18(2-3), 171-174.-   Maryanoff, B. E. and Reitz, A. B. Chemical Reviews, 1989, 89(4),    863-927.-   Kelly, S. E. in Comprehensive Organic Synthesis, Trost, B. M. and    Fleming, I. Ed.; Pergamon: Oxford, 1991, Vol. 1, pp. 729-817.-   Kolodiazhnyi, O. I., Phosphorus Ylides, Chemistry and Application in    Organic Synthesis; Wiley-VCH: New York, 1999.

Another carbon-carbon bond forming reaction that may be used to installthe lower chain is the Peterson olefination reaction, which is reviewedby Ager, D. J. Organic Reactions, 1990, 38, 1-223.

Aldehydes that may be used in the olefination step involved inpreparation of compounds of the present invention include, but are notlimited to, intermediates 13a-f, which can be generally prepared from(R)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one ((R)-8), as shown inScheme 3.

The hydroxyl moiety of intermediate (R)-8 may be protected (Step H) byreacting with ethyl vinyl ether (EVE) in the presence of TFA ortert-butyldimethylsilyl chloride (TBDMSCl) in the presence of a base,such as imidazole, to provide the EE-protected or TBS-protected species(9), respectively. N-alkylation of one of the protectedα,α-difluoropyrrolidone intermediates (9) with an alkylating agent, suchas one of 10a-f, affords the corresponding intermediate 11a-f (Step I).Alcohol deprotection (Step J) and subsequent controlled alcoholoxidation (Step K) provides the corresponding aldehyde intermediates13a-f that may be employed in the subsequent olefination step.

Aldehyde intermediate 13f may alternatively be acquired by thehydrogenation of protected alcohol intermediates 11d or 11e to 11f orthe unprotected alcohol intermediates 12d or 12e to 12f, followed by thesubsequent deprotection (for 11f) and controlled oxidation to 13f. Onehydrogenation reaction example is illustrated in Scheme 4.Palladium-catalyzed reduction of the internal carbon-carbon double bondof intermediate 12e (Scheme 4) to provide alcohol intermediate 12ffollowed by the controlled oxidation of the alcohol affords aldehydeintermediate 13f as illustrated in Scheme 3, Step K.

Detailed procedures for preparing the aldehyde intermediates isdescribed below.

Preparation of (R)-methyl7-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)heptanoate (13a)

Scheme 1, Step A: Preparation of (R)-methyl5-oxopyrrolidine-2-carboxylate (2) from(R)-5-oxopyrrolidine-2-carboxylic acid (1)

To a solution consisting of (R)-5-oxopyrrolidine-2-carboxylic acid(1,D-pyroglutamic acid from Chem-Impex International, 12.6 g, 97.4 mmol)in methanol (100 mL) was added sulfuric acid (1 mL) and the mixture wasstirred at room temperature for 24 hours. The solvent was evaporatedfrom the mixture, and the residue was purified by silica gelchromatography. Elution with acetone-dichloromethane (3:7 v/v) affordedthe title intermediate (13.3 g, 95%) as a clear oil; TLC R_(f) 0.42(solvent system: 3:7 v/v acetone-dichloromethane); ¹H-NMR (CDCl₃) δ 4.25(t, 1H), 3.73 (s, 3H), 2.5-2.2 (m, 4H).

Scheme 1, Step B: Preparation of (R)-5-(hydroxymethyl)pyrrolidin-2-one(3)

To a solution consisting of (R)-methyl 5-oxopyrrolidine-2-carboxylate(intermediate 2, 13.2 g, 115 mmol) in methanol (100 mL) at 0° C. wasadded sodium borohydride (10.5 g, 278 mmol) in portions. The reactionmixture was stirred at 0° C. until completion, at which time, aceticacid (3 mL) was added. The reaction mixture was concentrated and theresidue was purified on silica gel, eluting with methanol-chloroform(1:9 v/v) to afford the title intermediate (12.9 g, 97%) as a colorlesssolid; TLC R_(f) 0.33 (solvent system: 1:9 v/v methanol-chloroform);¹H-NMR (CDCl₃) δ 7.17 (s, 1H), 3.92 (s, 1H), 3.85-3.75 (m, 1H),3.64-3.40 (m, 2H), 2.42-2.35 (m, 2H), 2.2-2.05 (m, 1H), 1.88-1.7 (m,1H).

Scheme 1, Step C: Preparation of(R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (4)

To a solution consisting of (R)-5-hydroxymethyl-2-pyrrolidinone (AlfaAesar, 5.3 g, 46 mmol) in 2,2-dimethoxypropane (DMP) (40 mL, 326 mmol)was added camphorsulfonic acid (530 mg). The mixture was brought toreflux at 75° C. for 4 hours, and was subsequently concentrated invacuo. Fresh DMP (40 mL) was then added and the mixture was brought toreflux overnight. After concentration, the remaining residue waspurified by silica gel chromatography. Elution with ethylacetate-heptanes (1:2 v/v) afforded the title intermediate (3.6 g) as aclear oil; TLC R_(f) 0.20 (solvent system 50:50 v/v heptanes:ethylacetate); ¹H-NMR (CDCl₃) δ 4.3-4.2 (1H, m), 4.1 (1H, dd), 3.5 (1H, t),2.9-2.7 (1H, m), 2.6-2.5 (1H, m), 2.2-2.1 (1H, m), 1.9-1.7 (1H, m), 1.7(3H, s), 1.5 (3H, s); MS (ESI⁺) m/z 156.2 (M+1).

Scheme 1, Step C: First alternative preparation of(R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (4)

To a mixture consisting of (R)-5-hydroxymethyl-2-pyrrolidinone (20 g,174 mmol) in 2,2-dimethoxypropane (1.4 L, 11.400 mmol) was addedcamphorsulfonic acid (1.0 g, 4.3 mmol). The stirring mixture was heatedto 75° C. for 20 hours. The reaction mixture was treated with asaturated aqueous solution of sodium bicarbonate, diluted with water,and extracted with ethyl acetate. The combined organic phase was washedwith a saturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated. The residue was purified by silicagel chromatography. Elution with methanol-dichloromethane (1:70 v/v)afforded the title compound as a white solid (21.2 g, 78%); TLC R_(f)0.6 (solvent system: 25:75 v/v ethyl acetate-hexane); MS (ESI⁺) m/z156.1 (M+H)⁺, 178.1 (M+Na)⁺; ¹H-NMR (CDCl₃) δ 4.3-4.2 (m, 1H), 4.1 (dd,1H), 3.5 (t, 1H), 2.9-2.7 (m, 1H), 2.6-2.5 (m, 1H), 2.2-2.1 (m, 1H),1.9-1.7 (m, 1H), 1.7 (s, 3H), 1.5 (s, 3H).

Scheme 1, Step C: Second alternative preparation of(R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (4)

To a mixture consisting of (R)-5-hydroxymethyl-2-pyrrolidinone (50.0 g,434 mmol) in 2,2-dimethoxypropane (533 mL, 4300 mmol) was addedcamphorsulfonic acid (2.85 g, 10.8 mmol). The stirring mixture wasbrought to reflux at 88° C. for 1.5 hours, while removing methanol bydistillation. The reaction mixture was subsequently heated to 95° C. forone hour, cooled to room temperature, treated with triethylamine (5 mL),and stirred for 5 minutes. The mixture was then diluted withhexanes-ethyl acetate (500 mL, 1:3 v/v) and washed sequentially with a50% aqueous solution of sodium chloride and a saturated aqueous solutionof sodium chloride. The organic phase was dried over sodium sulfate,filtered, and concentrated. The residue was purified by crystallizationfrom hexanes to afford the title compound as white crystalline solid(30.48 g, 45%); TLC R_(f) 0.4 (solvent system: 5:95 v/vmethanol:dichloromethane) MS (ESI⁺) m/z 156.1 (M+H)⁺, 178.1 (M+Na)⁺;¹H-NMR (CDCl₃) δ 4.3-4.2 (m, 1H), 4.1 (dd, 1H), 3.5 (t, 1H), 2.9-2.7 (m,1H), 2.6-2.5 (m, 1H), 2.2-2.1 (m, 1H), 1.9-1.7 (m, 1H), 1.7 (s, 3H), 1.5(s, 3H).

Scheme 1, Step D: Preparation of(R)-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (5)

To a mixture consisting of diisopropylamine (6.5 mL, 46 mmol) and THF(75 mL) at −78° C. was added dropwise a solution of nBuLi (2.5 M inhexanes, 18 mL, 44 mmol), and the resulting solution stirred for onehour. A solution consisting of(R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (intermediate4, 3.6 g, 23 mmol) in THF (25 mL) was added dropwise, and the resultingsolution stirred for one hour. A solution consisting ofN-fluorobenzenesulfonimide (9.5 g, 30 mmol) in THF (50 mL) was addeddropwise, and the resulting solution was allowed to stir for 75 minutesbelow −55° C., and was subsequently quenched with the addition of asaturated aqueous ammonium chloride solution and warmed to roomtemperature. The organic material was extracted twice with ethylacetate. The combined organic phase was dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was dissolved in ethylacetate, filtered, and the filtrate was concentrated to a gold oil,which was purified by silica gel chromatography. Elution with ethylacetate:heptanes (1:3 v/v) afforded an approximately 1:1 mixture of thediastereomers of the title intermediate (1.54 g) as a clear oil; TLCR_(f) 0.40 (solvent system 50:50 v/v heptanes:ethyl acetate); ¹H-NMR(CDCl₃) δ 5.4-5.2 (m, 1H), 5.2-5.0 (m, 1H), 4.5-4.4 (m, 1H), 4.2-4.1 (m,2H), 4.0-3.9 (m, 1H), 3.5 (t, 1H), 3.4 (t, 1H), 2.8-2.7 (m, 1H), 2.5-2.3(m, 1H), 2.1-1.8 (m, 2H), 1.7 (s, 3H), 1.7 (s, 3H), 1.5 (s, 3H) 1.5 (s,3H); ¹⁹F-NMR (CDCl₃, 376 MHz) δ −102.2 (dd, ˜0.5F, J=264.2, 13.2 Hz),˜103.5 (ddd, ˜0.5F, J=264.3, 26.5, 14.6 Hz); MS (ESI⁺) m/z 174.1 (M+1).

Scheme 1, Step D: Alternative preparation of(7aR)-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (5)

To a solution consisting of(R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (intermediate4, 18.5 g, 119 mmol) in dry THF (400 mL) at −75° C. was added lithiumdiisopropylamide (74.5 mL, 149 mmol, 2 M in heptanes/THF/ethylbenzenefrom Sigma Aldrich) dropwise over 20 minutes, then stirred for one hour.The reaction mixture was then treated with a solution consisting ofN-fluorobenzenesulfonimide (56.6 g, 167 mmol, NFSi, from OakwoodChemical) in THF (300 mL) with steady addition over 30 minutes, and theresulting mixture was stirred for 16 hours, warming to room temperature.To the reaction mixture was added a saturated aqueous solution ofammonium chloride. The organic material was extracted twice with ethylacetate. The organic layer was washed with a 50% aqueous solution ofsodium chloride, followed by a saturated solution of sodium chloride,and dried over sodium sulfate, filtered, and concentrated. The residuewas redissolved in ethyl acetate (200 mL) and treated with heptane (200mL), causing the formation of a white precipitate. The precipitate wasfiltered and washed with 50% ethyl acetate in heptane. The combinedfiltrate was concentrated. The residue was dissolved in ethyl acetate(200 mL) and treated with heptane (200 mL), forming a secondprecipitate. The second precipitate was filtered and washed with 50%ethyl acetate in heptane. The filtrate was concentrated and the residue(31 g) was purified by silica gel chromatography. Elution with ethylacetate-hexanes (1:3 v/v) afforded pure samples of each of the twodiastereomers of the title compound as tan solids (4.1 g of each) and aportion of mixed diastereomers (3.8 g of an approximately 1:1 ratio).The total mass of the two diastereomer products isolated was 12.0 g (65%total yield).

(6S,7aR)-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(5.1α) and(6R,7aR)-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(5.1β)

Separation of the two isomers by chromatography, as described above,provided the two pure diastereomers.

(5.1α) TLC R_(f) 0.55 (solvent system: 60:40 v/v ethyl acetate-hexanes);HPLC on an Agilent 1100 instrument, ultraviolet detector at 210 nm,stationary phase Gemini 3μ C18, 50×2 mm column, mobile phase,water-methanol-acetic acid gradient over 4 min (90:10:0.1 to 10:90:0.1),retention time 2.33 minutes; MS (ESI⁺) m/z 174.1 (M+H)⁺; ¹H-NMR (CDCl₃)δ 5.085 (ddd, J=51.6, 6.0, 0.8 Hz, 1H) 4.5-4.4 (m, 1H), 4.15 (dd, 1H),3.4 (dd, 1H), 2.5-2.3 (m, 1H), 2.1-1.7 (m, 1H), 1.65 (s, 3H), 1.5 (s,3H); ¹⁹F-NMR (CDCl₃, 376 MHz) δ −184.5 (ddd, J=52, 41, 22 Hz, 1F).

(5.1β) TLC R_(f) 0.45 (solvent system: 60:40 v/v ethyl acetate-hexanes);HPLC on an Agilent 1100 instrument, ultraviolet detector at 210 nm,stationary phase Gemini 3μ C18, 50×2 mm column, mobile phase,water-methanol-acetic acid gradient over 4 min (90:10:0.1 to 10:90:0.1),retention time 1.69 minutes; MS (ESI⁺) m/z 174.1 (M+H)⁺; ¹H-NMR (CDCl₃)δ 5.325 (ddd, J=52.4, 9.9, 7.7 Hz, 1H) 4.2 (dd, 1H), 4.0-3.9 (m, 1H),3.5 (dd, 1H), 2.8-2.7 (m, 1H), 2.0-1.9 (m, 1H), 1.7 (s, 3H), 1.5 (s,3H); ¹⁹F-NMR (CDCl₃, 376 MHz) δ −185.9 (dd, J=52, 23 Hz, 1F).

Scheme 1, Step E: Preparation of(R)-6,6-difluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(6)

To a solution consisting of(7aR)-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (8.0g, 46.2 mmol, mixture of diastereomers of 5.1) in dry THF (300 mL) at−75° C. was added lithium bis(trimethylsilyl)amide (50.8 mL, 50.8 mmol,LiHMDS 1 M in THF) dropwise over ten minutes, then stirred for one hour.The reaction mixture was then treated with a solution consisting ofN-fluorobenzenesulfonimide (17.5 g, 55.4 mmol) in THF (100 mL) withsteady addition over ten minutes. The resulting mixture was stirred for30 minutes. Lithium bis(trimethylsilyl)amide (10.0 mL, 10 mmol) wasadded, and the reaction stirred for 16 hours, warming to roomtemperature. To the reaction mixture was added a 50% aqueous solution ofammonium chloride. The organic material was extracted with ethylacetate-heptane (5:1). The organic layer was washed sequentially with a50% aqueous solution of sodium chloride, water, and a saturated solutionof sodium chloride, then dried over sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel chromatography.Elution with ethyl acetate-hexanes (1:5 v/v) afforded the titlecompounds as a tan solid (7.39 g; 79%); TLC R_(f) 0.70 (solvent system:50:50 v/v ethyl acetate-hexanes); ¹H-NMR (CDCl₃) δ 4.3 (dd, 1H), 4.2-4.0(m, 1H), 3.5 (t, 1H), 2.9-2.7 (m, 1H), 2.2-2.0 (m, 1H), 1.7 (s, 3H), 1.5(s, 3H).

Scheme 1, Step E: Preparation of(R)-6,6-difluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(6)

To a mixture consisting of diisopropylamine (2.2 mL, 8.9 mmol) and THF(40 mL) at −78° C. was added dropwise a solution of nBuLi (2.5 M inhexanes, 6.0 mL, 15 mmol), and the resulting solution stirred for onehour. A solution consisting of(7aR)-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(intermediate 5, 1.54 g, 8.90 mmol) in THF (25 mL) was added dropwise,and the resulting solution stirred for one hour. A solution consistingof N-fluorobenzenesulfonimide (3.5 g, 11 mmol) in THF (25 mL) was addeddropwise, and the resulting mixture was allowed to stir for 75 minutesbelow −55° C. The reaction mixture was subsequently quenched with theaddition of a saturated aqueous ammonium chloride solution and warmed toroom temperature. The organic material was extracted twice with ethylacetate. The combined organic phase was dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was dissolved in ethylacetate, filtered, and the filtrate was concentrated to a gold oil whichwas purified by silica gel chromatography. Elution with ethylacetate:heptanes (1:5 v:v) afforded the title intermediate (1.28 g, 75%)as a clear oil; TLC R_(f) 0.60 (solvent system 50:50 v/v heptanes:ethylacetate); ¹H-NMR (CDCl₃) δ 4.3 (dd, 1H), 4.2-4.0 (m, 1H), 3.5 (t, 1H),2.9-2.7 (m, 1H), 2.2-2.0 (m, 1H), 1.7 (s, 3H), 1.5 (s, 3H); MS (ESI⁺)m/z 192.1 (M+1).

Scheme 1A, Step A: Alternative preparation of(R)-6,6-difluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(6)

To a mixture consisting of(R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (4) (15.5 g,100 mmol) in dry THF (300 mL) at −78° C. was added sec-butyllithium(78.5 mL, 110 mmol, 1.4 M in cyclohexane, from Sigma Aldrich) dropwiseover 5 minutes. The resulting reaction mixture was stirred for one hourand was subsequently treated with a mixture consisting ofN-fluorobenzene sulfonimide (35 g, 111 mmol, NFSi, from Oakwood) in THF(100 mL) with steady addition over five minutes. The resulting reactionmixture was stirred for another hour, after which time a lithiumbis(trimethylsilyl)amide solution (LiHMDS, 110 mL, 110 mmol, 1.0 M inTHF, from Sigma Aldrich) was added dropwise over five minutes. Theresulting reaction mixture was stirred for another hour, after whichtime a mixture consisting of NFSi (34.4 g, 109 mmol) in THF (100 mL) wasadded over five minutes. The resulting reaction mixture was stirred fortwo hours, after which time was added lithium bis(trimethylsilyl)amide(40 mL, 40 mmol, 1M in THF) to the −78° C. reaction mixture, which wassubsequently stirred for 30 minutes. The cooling bath was removed and asaturated aqueous solution of ammonium chloride added. The reactionmixture was allowed to warm to room temperature, and the organicmaterial was extracted with ethyl acetate. The organic layer wassequentially washed with water, a 50% saturated aqueous solution ofsodium chloride, and a saturated solution of sodium chloride, dried oversodium sulfate, filtered, and concentrated. The residue was purified bysilica gel chromatography. Elution with ethyl acetate-hexanes (1:3 v/v)afforded of the title compound as a solid (11.64 g; 61%); TLC R_(f) 0.4(solvent system: 5:95 v/v methanol-dichloromethane); ¹H-NMR (CDCl₃) δ4.3 (dd, 1H), 4.2-4.0 (m, 1H), 3.5 (t, 1H), 2.9-2.7 (m, 1H), 2.2-2.0 (m,1H), 1.7 (s, 3H), 1.5 (s, 3H).

Scheme 1, Step F: Preparation of (R)-methyl4-amino-2,2-difluoro-5-hydroxypentanoate (7)

To an ice-cooled solution consisting of(R)-6,6-difluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(intermediate 6, 1.28 g, 6.70 mmol) in methanol (20 mL) was addeddropwise 4N HCl in dioxane (3.0 mL, 12 mmol) and stirred at roomtemperature for 16 hours. The resulting mixture was concentrated and theproduct concentrate used without purification; TLC R_(f) 0.60 (solventsystem 93:7 v/v dichloromethane-methanol).

Scheme 1, Step G: Preparation of(R)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one ((R)-8)

To a solution consisting of (R)-methyl4-amino-2,2-difluoro-5-hydroxypentanoate (intermediate 7, 6.70 mmol) inTHF (25 mL) was added triethylamine (6 mL) and the reaction mixture wasstirred overnight. The reaction mixture was concentrated to give a cruderesidue, which was purified by silica gel chromatography. Elution withmethanol:dichloromethane (1:20 v/v) afforded the title intermediate (540mg) as a clear oil; TLC R_(f) 0.40 (solvent system 93:7 v/vdichloromethane:methanol); ¹H-NMR (CDCl₃) δ 3.7-3.6 (w, 1H), 3.6-3.4 (m,2H), 3.4-3.2 (m, 1H), 2.7-2.4 (m, 1H), 2.4-2.1 (m, 1H); MS (ESI⁺) m/z152.1 (M+1); (ESI⁻) m/z 150.1 (M−1).

Scheme 1A, Step B: Alternative preparation of(R)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one ((R)-8)

To a solution consisting of(R)-6,6-difluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one(intermediate 6, 12.5 g, 65.4 mmol) in water-1,4-dioxane (300 mL, 1:1v/v) was added Amberlite IR-120H* (6.23 g). The reaction mixture washeated to 115° C. for 6 hours and was subsequently filtered throughCelite and washed with methanol. The filtrate was concentrated underreduced pressure, using toluene and ethanol additives to help drive offwater, to provide a residue. The residue was washed with diethyl etherto afford the title compound as a tan solid (8.8 g; 89%), which wascarried on without further purification; TLC R_(f) 0.25 (solvent system:70:30 v/v ethyl acetate:hexanes).

*Amberlite IR-120H ion-exchange resin, strongly acid gel-type resin withsulfonic acid functionality, CAS: 39389-20-3.75 g of Amberlite waswashed and decanted three times with deionized water. The fourth washwas filtered using suction filtration and the semi-dry resin was quicklywashed with 2-propanol then diethyl ether. The resin was dried to give54 g of free flowing dark brown bead resin.

Scheme 3, Step H: Preparation of(5R)-5-((1-ethoxyethoxy)methyl)-3,3-difluoropyrrolidin-2-one (9; PG=EE)

To a solution consisting of(R)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one (intermediate 8, 540mg, 3.57 mmol) in dichloromethane (20 mL) and THF (10 mL) was addedethyl vinyl ether (1.4 mL, 15 mmol) followed by trifluoroacetic acid (20mg). The reaction mixture was stirred at room temperature for 16 hours.The reaction mixture was diluted with ethyl acetate (150 mL) and washedwith a saturated aqueous solution of sodium bicarbonate (10 mL) andbrine (5 mL) before being dried over sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel chromatography.Elution with methanol:dichloromethane (1:60 v/v) afforded the titleintermediate (726 mg) as a clear oil; TLC R_(f) 0.60 (solvent system:93:7 v/v dichloromethane:methanol); ¹H-NMR (CDCl₃) δ 4.8-4.6 (m, 1H),4.0-3.8 (m, 1H), 3.7-3.5 (m, 2H), 3.5-3.4 (m, 2H), 2.8-2.6 (m, 1H),2.4-2.2 (m, 1H), 1.3 (d, 3H), 1.2 (t, 3H); MS (ESI⁺) m/z 241.1 (M+NH₃),246.1 (M+Na); (ESI⁻) m/z 222.1 (M−1).

Scheme 3, Step H: Preparation of(R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoropyrrolidin-2-one(9; PG=TBS)

To a solution consisting of(R)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one (intermediate 8, 880mg, 3.57 mmol) in DMF (10 mL) and THF (10 mL) was addedtert-butyldimethylchlorosilane (1.40 g, 9.23 mmol) followed by imidazole(800 mg, 6.55 mmol). The reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was diluted with water(10 mL) and extracted thrice with ethyl acetate (55 ml, 2×25 ml). Thecombined organics were washed with 1:1 water:brine (3×10 mL) and brine(5 mL) before being dried over sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel chromatography.Elution with methanol:dichloromethane (1:50 v/v) afforded the titleintermediate (1528 mg, 99%) as a clear oil; TLC R_(f) 0.60 (solventsystem: 95:5 v/v dichloromethane-methanol); ¹H-NMR (CDCl₃) δ 3.8-3.7 (m,1H), 3.7-3.6 (m, 1H), 3.5-3.4 (m, 1H), 2.6-2.5 (m, 1H), 2.3-2.1 (m, 1H),0.8 (s, 9H), 0.0 (s, 6H); MS (ESI⁺) m/z 266.1 (M+1).

Scheme 3, Step I: Preparation of methyl7-((5R)-5-((1-ethoxyethoxy)methyl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoate(11a)

To a suspension consisting of sodium hydride (60% in mineral oil, 18 mg,0.45 mmol) and sodium iodide (74 mg, 0.49 mmol) in DMF (5 mL) was addeddropwise a solution of(5R)-5-((1-ethoxyethoxy)methyl)-3,3-difluoropyrrolidin-2-one(intermediate 9; PG=EE, 100 mg, 0.45 mmol) in DMF (5 mL). The mixturewas stirred at room temperature for two hours followed by 50° C. for 30minutes. To the reaction mixture was added dropwise methyl7-bromoheptanoate (10a, Alfa Aesar, 120 mg, 0.538 mmol) and stirringcontinued overnight at 50° C. The mixture was diluted with ethyl acetate(200 mL) and washed sequentially with 0.5N hydrochloric acid (20 mL), a5% aqueous solution of sodium thiosulfate (10 mL), 50% brine (4×25 mL),and brine (25 mL). The organic phase was dried over sodium sulfate,filtered, and concentrated. The residue was purified by silica gelchromatography. Elution with methanol:dichloromethane (1:100 v/v)afforded the title intermediate (128 mg, 78%) as a clear oil; TLC R_(f)0.95 (solvent system: 93:7 v/v dichloromethane:methanol); ¹H-NMR (CDCl₃)δ 4.7 (dq, 1H), 3.85-3.75 (m, 1H), 3.75-3.4 (m, 8H), 3.15-3.05 (m, 1H),2.65-2.35 (m, 1H), 2.3 (t, 2H), 1.7-1.4 (m, 4H), 1.4-1.3 (m, 4H), 1.3(d, 3H), 1.2 (t, 3H); MS (ESI⁺) m/z 383.2 (M+NH₃), 388.1 (M+Na).

Alternative Preparation of 11a

To a suspension consisting of sodium hydride (60% in mineral oil, 108mg, 2.7 mmol) and sodium iodide (450 mg, 3.0 mmol) in DMF (30 mL) wasadded dropwise a solution consisting of(5R)-5-((1-ethoxyethoxy)methyl)-3,3-difluoropyrrolidin-2-one(intermediate 9; PG=EE, 600 mg, 2.68 mmol) in DMF (30 mL). The reactionmixture was stirred at room temperature for two hours followed by 50° C.for 30 minutes. To the reaction mixture was added dropwise methyl7-bromoheptanoate (available from Alfa Aesar, 720 mg, 2.23 mmol) andstirring continued overnight at 50° C. The mixture was diluted withethyl acetate and washed sequentially with 0.5 N hydrochloric acid, a 5%aqueous solution of sodium thiosulfate, 50% saturate aqueous solution ofsodium chloride, and saturate aqueous solution of sodium chloride. Theorganic phase was dried over sodium sulfate, filtered, and concentrated.The residue was purified by silica gel chromatography. Elution withmethanol:dichloromethane (1:125 v/v) afforded the title intermediate(888 mg, 90%) as a tan solid; TLC R_(f) 0.95 (solvent system: 93:7 v/vdichloromethane-methanol); MS (ESI⁺) m/z 383.2 (M+NH₄)⁺, 388.1 (M+Na)⁺.

Scheme 3, Step J: Preparation of (R)-methyl7-(3,3-difluoro-5-(hydroxymethyl)-2-oxopyrrolidin-1-yl)heptanoate (12a)

To a solution consisting of methyl7-((5R)-5-((1-ethoxyethoxy)methyl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoate(intermediate 11a, 113 mg, 0.310 mmol) in methanol (10 mL) was addedp-toluenesulfonic acid monohydrate (2 mg) and the mixture was stirred atroom temperature for 18 hours. The reaction mixture was concentrated togive a crude residue that was purified by silica gel chromatography.Elution with methanol-dichloromethane (1:80 v/v) afforded the titleintermediate (86 mg, 95%) as a pale yellow oil; TLC R_(f) 0.55 (solventsystem: 7:93 v/v methanol-dichloromethane); ¹H-NMR (CDCl₃) δ 3.85-3.6(m, 4H), 3.65 (s, 3H), 3.2-3.1 (m, 1H), 2.6-2.4 (m, 2H), 2.3 (t, 2H),1.7-1.4 (m, 4H), 1.4-1.2 (m, 4H); MS (ESI⁺) m/z 311.2 (M+NH₄), 316.1(M+Na).

Scheme 3, Step K: Preparation of (R)-methyl7-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl) heptanoate (13a)

To a solution consisting of (R)-methyl7-(3,3-difluoro-5-(hydroxymethyl)-2-oxopyrrolidin-1-yl)heptanoate(intermediate 12a, 85 mg, 0.29 mmol) in dichloromethane (10 ml) wasadded Dess-Martin periodinate (150 mg, 0.348 mmol), and the reactionmixture was stirred for four hours. The reaction mixture was filteredand the filtrate was subsequently concentrated. Without further workup,the residue was purified by silica gel chromatography. Elution withmethanol-dichloromethane (1:200 v/v) afforded the title intermediate(76.6 mg, 91%) as a pale yellow oil; TLC R_(f) 0.60 (solvent system:7:93 v/v methanol-dichloromethane).

Preparation of (R)-methyl4-(2-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)ethyl)benzoate (13b)

Scheme 3, Step I: Preparation of (R)-methyl4-(2-(5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoro-2-oxopyrrolidin-1-yl)ethyl)benzoate(11b; PG=TBS)

To a suspension consisting of sodium hydride (60% in mineral oil, 61 mg,1.5 mmol) and sodium iodide (251 mg, 1.67 mmol) in DMF (40 mL) was addeddropwise a solution consisting of(R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoropyrrolidin-2-one(intermediate 9; PG=TBS, 370 mg, 1.39 mmol) in DMF (5 mL). The mixturewas stirred at room temperature for two hours followed by 50° C. for 30minutes. To the reaction mixture was added dropwise methyl4-(2-bromoethyl)benzoate (406 mg, 1.67 mmol) in DMF (5 mL), and stirringcontinued overnight at 50° C. The mixture was diluted with ethyl acetateand washed sequentially with 0.5 N hydrochloric acid, a 5% aqueoussolution of sodium thiosulfate, 50% brine, and brine. The organic phasewas dried over sodium sulfate, filtered, and concentrated. The residuewas purified by silica gel chromatography. Elution with ethylacetate:heptane (increasing solvent strength, 1:50 v/v to 1:10 v/v)followed by eluting with methanol-dichloromethane (1:50 v/v) affordedthe title intermediate (39 mg, 6.6%); TLC R_(f) 0.6 (solvent system:70:30 v/v heptane:ethyl acetate); ¹H-NMR (CDCl₃) δ 7.9 (d, 2H), 7.28 (d,2H), 3.98-3.91 (m, 1H), 3.9 (s, 3H), 3.74-3.48 (m, 2H), 3.46-3.35 (m,2H), 3.1-2.9 (m, 2H), 2.48-2.18 (m, 2H), 0.8 (s, 9H), 0.0 (s, 6H); MS(ESI⁺) m/z 445.1 (M+NH₃).

Significant improvement of the yield (in relation to(R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoropyrrolidin-2-one)was realized by repeated additions of sodium hydride and methyl4-(2-bromoethyl)benzoate to the reaction mixture.

Scheme 3, Step J: (R)-methyl4-(2-(3,3-difluoro-5-(hydroxymethyl)-2-oxopyrrolidin-1-yl)ethyl)benzoate(12b)

To a solution consisting of (R)-methyl4-(2-(5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoro-2-oxopyrrolidin-1-yl)ethyl)benzoate(11b, 180 mg, 0.42 mmol) in THF (10 mL) was added tetrabutylammoniumfluoride (0.55 mL, 1M in THF), and the reaction mixture was stirredovernight. The reaction mixture was diluted with ethyl acetate andwashed with 1:1 brine-water (3×15 mL) and once with brine. The organicphase was dried over sodium sulfate, filtered, and concentrated. Thecrude residue was purified by silica gel chromatography. Elution withmethanol-dichloromethane (increasing solvent strength, 1:200 v/v to 1:30v/v) afforded the title intermediate (147 mg); TLC R_(f) 0.5 (solventsystem: 5:95 v/v methanol-dichloromethane); ¹H-NMR (CDCl₃) δ 7.9 (d,2H), 7.24 (d, 2H), 3.98-3.91 (m, 1H), 3.87 (s, 3H), 3.74-3.48 (m, 2H),3.51-3.46 (m, 2H), 3.1-2.8 (m, 2H), 2.48-2.22 (m, 2H); MS (ESI⁺) m/z 331(M+⁺NH₄).

Scheme 3, Step K: Preparation of (R)-methyl4-(2-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)ethyl)benzoate (13b)

(R)-methyl4-(2-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)ethyl)benzoate wasprepared from 12b using the oxidation procedure (Step K) described forthe preparation of intermediate 13a from intermediate 12a; TLC R_(f) 0.4(solvent system: 95:5 v/v dichloromethane-methanol); ¹H-NMR (CDCl₃) δ9.2 (s, 1H), 7.9 (dd, 2H), 7.24 (dd, 2H), 3.98-3.91 (m, 1H), 3.87 (s,3H), 3.74-3.48 (m, 2H), 3.51-3.46 (m, 2H), 3.1-2.8 (m, 2H), 2.48-2.22(m, 2H).

Preparation of (R)-methyl5-(3-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)prop-1-yn-1-yl)thiophene-2-carboxylate(13d)

(R)-Methyl5-(3-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)prop-1-yn-1-yl)thiophene-2-carboxylateis prepared in the manner as that described for the preparation ofintermediate 13a except that methyl5-(3-bromoprop-1-yn-1-yl)thiophene-2-carboxylate (10d) is used in Step Iinstead of methyl 7-bromoheptanoate.

Preparation of (R,Z)-methyl5-(3-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)prop-1-en-1-yl)thiophene-2-carboxylate(13e)

(R,Z)-Methyl5-(3-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)prop-1-en-1-yl)thiophene-2-carboxylateis prepared in the manner as that described for the preparation ofintermediate 13a except that (Z)-methyl5-(3-bromoprop-1-en-1-yl)thiophene-2-carboxylate (10e) is used in Step Iinstead of methyl 7-bromoheptanoate.

Preparation of (R)-methyl5-(3-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(13f)

Preparation of methyl 5-bromothiophene-2-carboxylate

To an iced-cooled solution consisting of 5-bromo-2-thiophene carboxylicacid (Oakwood Products, 5.1 g, 25 mmol) in ethyl acetate (200 mL) andmethanol (20 mL) was added TMS diazomethane (2M in diethyl ether, 20 ml,40 mmol) over 20 minutes. Gas evolution was observed and the reactionmixture was stirred for one hour. The mixture was then allowed to warmto room temperature overnight. The volatile material was removed and theresidue was purified by silica gel chromatography. Elution with ethylacetate-heptane (1:50 v/v) afforded the title intermediate (5.4 g, 98%)as a white solid; TLC R_(f) 0.60 (solvent system 90:10 v/vheptanes:ethyl acetate); ¹H-NMR (CDCl₃) δ 7.5 (d, 1H), 7.1 (d, 1H), 4.9(s, 3H).

Preparation of methyl 5-(3-hydroxyprop-1-yn-1-yl)thiophene-2-carboxylate

To a solution consisting of methyl 5-bromo-2-thiophene carboxylate (5.4g, 24 mmol) in benzene (60 mL) was addedtetrakis(triphenylphosphine)palladium (0) (676 mg, 0.6 mmol) and thereaction mixture was stirred for 30 minutes. To the reaction mixture wasthen added, quickly in one portion, a solution consisting of copperiodide (360 mg, 1.8 mmol) and n-butylamine (5.0 ml, 48 mmol in benzene(10 mL) followed by slow addition of propargyl alcohol (2.2 mL, 36 mmol)in benzene (30 ml) over 15 minutes. The reaction mixture was stirred forfive days and was quenched with a saturated solution of ammoniumchloride (200 mL). The organic material was extracted with diethyl ether(3×300 mL). The combined organic phase was washed with water (100 mL)and brine (2×50 mL) before drying over sodium sulfate and concentratingto a dark brown oil. The residue was purified by silica gelchromatography. Elution with ethyl acetate-heptane- (1:9 v:v) affordedthe title intermediate (4.39 g, 93%); TLC R_(f) 0.7 (solvent system50:50 v/v heptanes:ethyl acetate); ¹H-NMR (CDCl₃). δ 7.6 (d, 1H), 7.1(d, 1H), 4.5 (s, 2H), 3.9 (s, 3H), 2.0 (br t, 1H).

Preparation of methyl 5-(3-hydroxypropyl)thiophene-2-carboxylate

To a solution consisting of methyl5-(3-hydroxyprop-1-yn-1-yl)thiophene-2-carboxylate (700 mg, 3.57 mmol)in methanol (10 ml) was added palladium on calcium carbonate, 5% (2.0g). The reaction atmosphere was replaced with hydrogen and the reactionmixture was stirred vigorously for two hours. The mixture was thenfiltered through Celite and the solvent removed. The residue waspurified by silica gel chromatography. Elution withmethanol-dichloromethane (1:100 v:v) afforded the title intermediate(650 mg, 91%); TLC R_(f) 0.60 (solvent system 93:7 v/vdichloromethane-methanol); ¹H-NMR (CDCl₃) δ 7.2 (d, 1H), 6.8 (d, 1H),3.9 (s, 3H), 3.7 (t, 2H), 2.9 (t, 2H), 2.0-1.9 (m, 2H), 1.8-1.7 (br m,1H); MS (ESI⁺) m/z 201.1 (M+1), 223.0 (M+Na).

Preparation of methyl 5-(3-bromopropyl)thiophene-2-carboxylate (10f)

To a solution consisting of methyl5-(3-hydroxypropyl)thiophene-2-carboxylate (633 mg, 3.17 mmol) indichloromethane (25 mL) at 0° C. was added carbon tetrabromide (1.56 g,4.43 mmol) and triphenylphosphine (1.23 g, 4.43 mmol). The reactionmixture was stirred for two hours. The solvent was removed and theresidue was purified by silica gel chromatography. Elution with ethylacetate-heptane (1:20 v:v) afforded the title intermediate (2.56 g); TLCR_(f) 0.60 (solvent system 75:25 v/v heptane-ethyl acetate); MS (ESI+)m/z 263.0 (M+1); ¹H-NMR (CDCl₃) δ 7.6 (d, 1H), 6.8 (d, 1H), 3.9 (s, 3H),3.85 (t, 2H), 2.95 (t, 2H), 2.0-1.9 (m, 2H).

Alternative preparation of methyl5-(3-bromopropyl)thiophene-2-carboxylate (10f)

Preparation of 5-(3-bromopropyl)thiophene-2-carboxylic acid

To a solution consisting of thienoic acid (10 g, 78 mmol) in THF (150mL) at −78° C. was added an LDA solution (85 mL, 170 mmol, 2 M inheptanes/THF/ethylbenzene, Sigma-Aldrich) dropwise over 20 minutes, andthe reaction mixture was stirred 40 minutes. To the reaction mixture wasthen added dibromopropane (23.8 g, 117 mmol) in one portion, and thereaction mixture was allowed to warm to room temperature and was stirredfor 3 days. To the reaction mixture was added 50 mL each of a saturatedaqueous solution of ammonium chloride, a saturated aqueous solution ofsodium chloride, and 6 N HCl. The organic material was extracted withethyl acetate and the organic layer was dried over sodium sulfate,filtered, and concentrated to afford the title compound as a yellow oil(24.0 g). The product was used without further purification; TLC R_(f)0.5 (solvent system: 30:70:1 v/v ethyl acetate-hexanes-acetic acid).

Preparation of methyl 5-(3-bromopropyl)thiophene-2-carboxylate (10f)

To a solution consisting of 5-(3-bromopropyl)thiophene-2-carboxylic acid(from procedure above, 24 g, 78 mmol) in ethyl acetate (150 mL) andmethanol (15 mL) at 0° C. was added TMS-diazomethane (50 mL, 100 mmol, 2M) dropwise over one hour. The reaction mixture was then allowed to warmto room temperature and was stirred for 16 hours, The reaction mixturewas concentrated under reduced pressure without workup. The residue waspurified by silica gel chromatography. Elution with ethylacetate-heptane (1:80 v/v) afforded the title compound as a white solid(4.95 g; 24% over two steps); TLC R_(f) 0.45 (solvent system: 15:85 v/vethyl acetate-hexanes); MS (ESI⁺) m/z 263, 265 (isotopic bromines, each(M+H)⁺); ¹HNMR (CDCl₃) δ 7.5 (d, 1H), 6.7 (d, 1H), 3.75 (s, 3H), 3.3 (t,2H), 2.9 (t, 2H), 2.1-2.0 (m, 2H).

Scheme 3, Step I: Preparation of (R)-methyl5-(3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoro-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(11f; PG=TBS)

To a suspension consisting of sodium hydride (60% in mineral oil, 458mg, 11.5 mmol) and sodium iodide (1.79 g, 12.0 mmol) in DMF (60 mL) wasadded dropwise a solution consisting of(R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoropyrrolidin-2-one(5; PG=TBS, 2.9 g, 10.9 mmol) in DMF (10 mL). The mixture was stirred atroom temperature for 90 minutes, after which time was added dropwise amixture consisting of methyl 5-(3-bromopropyl)thiophene-2-carboxylate(10f, 3.16 g, 12.0 mmol, preparation described above) in DMF, andstirring was continued at 50° C. for 16 hours. The mixture was treatedwith an aqueous solution of ammonium chloride and extracted with 2:1ethyl acetate-heptane. The combined organics were washed with a 50%saturated aqueous solution of sodium chloride, followed by a saturatedaqueous solution of sodium chloride, and was dried over sodium sulfate.The residue was purified by silica gel chromatography. Elution withethyl acetate-heptane (1:5 v/v) afforded the title intermediate (4.6 g;93%); TLC R_(f) 0.30 (solvent system: 75:25 v/v heptanes:ethyl acetate);¹H-NMR (CDCl₃) δ 7.6 (d, 1H), 6.8 (d, 1H), 3.8 (s, 3H), 3.7-3.6 (m, 1H),3.6-3.5 (m, 1H), 3.3-3.1 (m, 1H), 2.8 (t, 2H), 2.6-2.4 (m, 1H), 2.4-2.2(m, 1H), 2.0 (s, 3H), 1.2 (t, 1H), 0.8 (s, 9H), 0.0 (s, 6H); MS (ESI⁺)m/z 465.1 (M+NH₄)⁺.

Scheme 3, Step J: Preparation of (R)-methyl5-(3-(3,3-difluoro-5-(hydroxymethyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(12f)

To a solution consisting of (R)-methyl5-(3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoro-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(11f; PG=TBS, 5.15 g, 11.5 mmol) in THF (20 mL) was added TBAF (1 M inTHF, 14.96 mL, 14.96 mmol) over two hours and the mixture was stirred atroom temperature for 16 hours. The mixture was treated with an aqueoussolution of ammonium chloride and extracted with ethyl acetate. Thecombined organic phase was washed with a 50% saturated aqueous solutionof sodium chloride, followed by a saturated aqueous solution of sodiumchloride and was dried over sodium sulfate, filtered, and concentrated.The residue was purified by silica gel chromatography. Elution withmethanol-dichloromethane (1:80 v/v) afforded the title intermediate as apale yellow oil (3.4 g; 88%); TLC R_(f) 0.5 (solvent system: 5:95 v/vmethanol-dichloromethane); ¹H-NMR (CDCl₃) δ 7.6 (d, 1H), 6.8 (d, 1H),3.85 (s, 3H), 3.8-3.6 (m, 4H), 3.3-3.1 (m, 1H), 2.85 (t, 2H), 2.6-2.4(m, 2H), 2.1-1.9 (m, 2H); MS (ESI⁺) m/z 351.0 (M+NH₄)⁺.

Scheme 3, Step J: Alternative preparation of (R)-methyl5-(3-(3,3-difluoro-5-(hydroxymethyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(12f)

To a solution consisting of (R)-methyl5-(3-(5-(((tert-butyldimethylsilyl)oxy)methyl-3,3-difluoro-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(11f; PG=TBS, 305 mg, 0.682 mmol) in methanol (10 mL) was added 1 M HCl(1 mL) and the reaction mixture was stirred overnight. The mixture wasconcentrated under reduced pressure to provide a residue, which waspurified by silica gel chromatography. Elution with 5:95 (v/v)methanol-dichloromethane afforded the title intermediate (178 mg, 78.4%)as an oil; TLC R_(f) 0.4, solvent system: 5:95 (v/v)methanol-dichloromethane.

Scheme 3, Step K: Preparation of (R)-methyl5-(3-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(13f)

(R)-Methyl5-(3-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewas prepared from 12f using the oxidation procedure (Step K) describedfor the preparation of intermediate 13a from intermediate 12a to affordthe title intermediate (80 mg) as a pale yellow oil; TLC R_(f) 0.60(solvent system: 7:93 v/v methanol-dichloromethane).

Organic β-keto phosphonate esters such as

may be used as reaction coupling partners with aldehydes such as 13a-fin a Horner-Emmons-Wadsworth-type process to install the lactamlower-chain scaffold. Such β-keto phosphonate esters may be prepared bycoupling an appropriate carboxylic ester

with lithiated/deprotonated dialkyl methylphosphonate according to thegeneral reaction illustrated in Scheme 6 and variations thereof. TablesA-P/Q of Lower Chains (below) describe various lower-chain components Bof the exemplary embodiments.

Carboxylic esters 14 may be commercially available or prepared fromcommercially-available starting materials as shown in Schemes 7a-g. Thenumbering system, comprising various numerical, lower-case alphabetical,and lower-case Roman numeral descriptors, for intermediates comprisingcomponent B, such as carboxylic esters 14, β-keto phosphonate esters 15,NHS esters 18, amides 19, carboxylic acids 20, and(S)-3-(B-carbonyl)-4-benzyloxazolidin-2-ones 21 found in Schemes,Tables, and Examples herein shall be interpreted as follows:

A carboxylic ester, 14(a-o)a or 14(a-o)b/c(i-viii), may be prepared intwo steps from commercially available diethyl malonate or an appropriatecommercially available diethyl 2-(C₁-C₄ alkyl) malonate startingmaterial. Reaction of the malonate starting material with an appropriatelithium amide base, such as LDA or LiHMDS, or an appropriate hydridebase, such as sodium hydride, or alkoxide base, such as sodium ethoxide,followed with an appropriate alkylating agent R⁶—X¹, as illustrated inScheme 7a, Step A, affords the corresponding 2-R⁶-substituted diethylmalonate 16. Subsequent decarboxylation (Step B) provides thecorresponding carboxylic ester intermediate 14, wherein both R⁴ and R⁵are hydrogen, or wherein one of R⁴ and R⁵ is a C₁-C₄ alkyl group (alkylgroups (i) through (viii) represent methyl, ethyl, n-propyl, 2-propyl,n-butyl, iso-butyl, sec-butyl, and tert-butyl, respectively) and theother is a hydrogen. Examples of commercially available diethyl (C₁-C₄alkyl) malonates include diethyl methyl malonate, diethyl ethylmalonate, diethyl isopropyl malonate, diethyl n-propyl malonate, diethyln-butyl malonate (all from Sigma-Aldrich, Acros Organics, or AlfaAesar), diethyl isobutyl malonate, and diethyl sec-butyl malonate (bothfrom Alfa Aesar). Methods for preparing the starting diethyl (C₁-C₄alkyl) malonates are known in the art; for example, diethyl malonate maybe combined with a base such as potassium carbonate and an appropriatealkylating agent such as methyl iodide, ethyl iodide, n-propyl bromide,or n-butyl bromide under microwave irradiation in the method describedby Keglevich et al. in Letters in Organic Chemistry, 2008, 5(3), 224-228and in Green Chemistry, 2006, 8(12), 1073-1075. Other methods that maybe used to prepare the diethyl (C₁-C₄ alkyl) malonates include thereaction of diethyl malonate with an appropriate alkylating agent suchas ethyl iodide, isopropyl bromide, isobutyl bromide, or sec-butylbromide in the presence of a base such as sodium ethoxide in an organicsolvent such as ethanol as described in Patel and Ryono in Bioorganicand Medicinal Chemistry Letters, 1992, 2(9), 1089-1092 and elsewhere.

Carboxylic ester intermediates 14 possessing a gem-dimethyl substitutionat the carbon atom a to the ester carbonyl group (both R⁴ and R⁵ aremethyl), such as 14(a-o)d(i), may be prepared by the methylation of thecorresponding mono-α-methyl ester intermediate (stereochemical mixture)14(a-o)b/c(i) as shown in Scheme 7b and reported in Shibasaki, M. et al,in Chemical and Pharmaceutical Bulletin, 1989, 37(6), 1647-1649.

Scheme 7c illustrates mono-alkylations of commercially available orprepared carboxylic esters 14(a-o)a with an alkylating agent R⁴/R⁵—X¹,wherein the R⁴/R⁵ group is a C₁-C₄ alkyl group and X¹ is a leaving groupsuch as iodide or bromide to provide the corresponding mono-alkylatedanalogs 14(a-o)b/c, respectively. The mono-alkylated carboxylic esteranalogs may be alkylated a second time; for example, mono-methylatedcarboxylic acid esters (stereochemical mixture) 14(a-o)b/c(i) may bemethylated a second time to provide the corresponding gem-dimethylsubstituted esters 14(a-o)d(i), as illustrated in Scheme 7d.

Scheme 7e illustrates the preparation of 1-R⁶-substituted C₃-C₅cycloalkylcarboxylic acids and their C₁-C₄ alkyl esters 14(a-o)e(ix-xi).Similar transformations are described in Yang, D. et. al. in Journal ofOrganic Chemistry, 2009, 74(22), 8726-8732; Cowling, S. J. and Goodby,J. W. in Chemical Communications (Cambridge, United Kingdom), 2006, 39,4107-4709; Araldi, G. L. et. al. in WO 2003/103604; and others.

Stereopure carboxylic esters 14(a-o)b(i-viii) and their stereoisomers,14(a-o)c(i-viii) may be prepared according to the route illustrated inScheme 7f. Alkylation of an appropriately-substituted carboxylic acidstarting material, such as propionic acid (R⁴/R⁵ is a methyl group), atthe carbon position alpha to the acid carbonyl group by treatment of theacid with an appropriate base, such as lithium diisopropylamide (abouttwo molar equivalents) in the presence of a suitable solvent, such asTHF, with an alkylating agent R⁶—X¹ (Step A) provides the correspondingcarboxylic acid intermediates 20(a-o)b/c(i-viii). Subsequent coupling ofthe carboxylic acid intermediate with N-hydroxysuccinimide (NHS) formsthe corresponding NHS ester (an activated ester) stereoisomeric mixture18(a-o)b/c(i-viii) (Step B). Treatment of the activated esterstereoisomeric mixture 18(a-o)b/c(i-vii) with(R)-2-amino-2-phenylethanol in THF results in the mixture of two amidediastereomers 19(a-o)b(i-viii) and 19(a-o)c(i-viii) (Step C), which maybe separated by chromatography to provide each pure diastereomer (StepD). Recrystallization of the individual diastereomers may provide amideswith even greater de purity. Amide hydrolysis of each diastereomer toits corresponding carboxylic acid 20(a-o)b(i-viii) and 20(a-o)c(i-viii),respectively (Step E), and subsequent esterification (Step F) providescorresponding individual carboxylic ester stereoisomers 14(a-o)b(i-viii)and 14(a-o)c(i-viii), respectively.

Scheme 7g shows a synthetic pathway to stereopure carboxylic esters14(a-o)b(i -vii) (R⁵ is hydrogen) employing the use of the chiralauxiliary to generate “(S)-3-(B-carbonyl)-4-benzyloxazolidin-2-ones”21(a-o)a (both R⁴ and R⁵ are hydrogen) for more-efficient (asymmetric)alkylation in Step C to provide the corresponding alkylated.“(S)-3-(B-carbonyl)-4-benzyloxazolidin-2-ones” analogs enriched in the21(a-o)b(i-vii) stereoisomer over the 21(a-o)c(i-vii) stereoisomer.Removal of the chiral auxiliary (Step D) following alkylation andsubsequent chiral amide derivatization (Steps E and F) provides thediastereomers 19(a-o)b(i-vii) separable by chromatography and furtherpurified by crystallization (Step G). Acid-catalyzed amide hydrolysis(Step H) to the corresponding stereopure carboxylic acid 20(a-o)b(i-vii)and subsequent esterification (Step I) provide the desired stereopurecarboxylic ester intermediates 14(a-o)b(i-vii), which can be carriedonto their corresponding stereopure β-keto phosphonate esters15(a-o)b(i-vii).

Scheme 8 illustrates the conversions of acetylenic carboxylic esters14(a-f)a and 14(a-f)(b-e)(i-xi) to the corresponding β-keto phosphonatesby the previously-described general manner (Step A) and subsequentcatalytic hydrogenation (Step B) to provide the corresponding saturatedanalogs.

Table A of Lower Chains B R⁴ R⁵ R⁶ aa H H

ab(i) Me H ac(i) H Me ad(i) Me Me ab(ii) Et H ac(ii) H Et ad(ii) Et Etab(iii) n-Pr H ac(iii) H n-Pr ad(iii) n-Pr n-Pr ab(iv) i-Pr H ac(iv) Hi-Pr ad(iv) i-Pr i-Pr ab(v) n-Bu H ac(v) H n-Bu ad(v) n-Bu n-Bu ab(vi)i-Bu H ac(vi) H i-Bu ad(vi) i-Bu i-Bu ab(vii) sec-Bu H ac(vii) H sec-Buad(vii) sec-Bu sec-Bu ab(viii) tert-Bu H ac(viii) H tert-Bu ad(viii)tert-Bu tert-Bu ae(ix)

ae(x)

ae(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table B of Lower Chains B R⁴ R⁵ R⁶ ba H H

bb(i) Me H bc(i) H Me bd(i) Me Me bb(ii) Et H bc(ii) H Et bd(ii) Et Etbb(iii) n-Pr H bc(iii) H n-Pr bd(iii) n-Pr n-Pr bb(iv) i-Pr H bc(iv) Hi-Pr bd(iv) i-Pr i-Pr bb(v) n-Bu H bc(v) H n-Bu bd(v) n-Bu n-Bu bb(vi)i-Bu H bc(vi) H i-Bu bd(vi) i-Bu i-Bu bb(vii) sec-Bu H bc(vii) H sec-Bubd(vii) sec-Bu sec-Bu bb(viii) tert-Bu H bc(viii) H tert-Bu bd(viii)tert-Bu tert-Bu be(ix)

be(x)

be(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table C of Lower Chains B R⁴ R⁵ R⁶ ca H H

cb(i) Me H cc(i) H Me cd(i) Me Me cb(ii) Et H cc(ii) H Et cd(ii) Et Etcb(iii) n-Pr H cc(iii) H n-Pr cd(iii) n-Pr n-Pr cb(iv) i-Pr H cc(iv) Hi-Pr cd(iv) i-Pr i-Pr cb(v) n-Bu H cc(v) H n-Bu cd(v) n-Bu n-Bu cb(vi)i-Bu H cc(vi) H i-Bu cd(vi) i-Bu i-Bu cb(vii) sec-Bu H cc(vii) H sec-Bucd(vii) sec-Bu sec-Bu cb(viii) tert-Bu H cc(viii) H tert-Bu cd(viii)tert-Bu tert-Bu ce(ix)

ce(x)

ce(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table D of Lower Chains B R⁴ R⁵ R⁶ da db(i) dc(i) dd(i) H Me H Me H H MeMe

db(ii) Et H dc(ii) H Et dd(ii) Et Et db(iii) n-Pr H dc(iii) H n-Prdd(iii) n-Pr n-Pr db(iv) i-Pr H dc(iv) H i-Pr dd(iv) i-Pr i-Pr db(v)n-Bu H dc(v) H n-Bu dd(v) n-Bu n-Bu db(vi) i-Bu H dc(vi) H i-Bu dd(vi)i-Bu i-Bu db(vii) sec-Bu H dc(vii) H sec-Bu dd(vii) sec-Bu sec-Budb(viii) tert-Bu H dc(viii) H tert-Bu dd(viii) tert-Bu tert-Bu de(ix)

de(x)

de(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table E of Lower Chains B R⁴ R⁵ R⁶ ea eb(i) ec(i) ed(i) H Me H Me H H MeMe

eb(ii) Et H ec(ii) H Et ed(ii) Et Et eb(iii) n-Pr H ec(iii) H n-Pred(iii) n-Pr n-Pr eb(iv) i-Pr H ec(iv) H i-Pr ed(iv) i-Pr i-Pr eb(v)n-Bu H ec(v) H n-Bu ed(v) n-Bu n-Bu eb(vi) i-Bu H ec(vi) H i-Bu ed(vi)i-Bu i-Bu eb(vii) sec-Bu H ec(vii) H sec-Bu ed(vii) sec-Bu sec-Bueb(viii) tert-Bu H ec(viii) H tert-Bu ed(viii) tert-Bu tert-Bu ee(ix)

ee(x)

ee(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table F of Lower Chains B R⁴ R⁵ R⁶ fa fb(i) fc(i) fd(i) H Me H Me H H MeMe

fb(ii) Et H fc(ii) H Et fd(ii) Et Et fb(iii) n-Pr H fc(iii) H n-Prfd(iii) n-Pr n-Pr fb(iv) i-Pr H fc(iv) H i-Pr fd(iv) i-Pr i-Pr fb(v)n-Bu H fc(v) H n-Bu fd(v) n-Bu n-Bu fb(vi) i-Bu H fc(vi) H i-Bu fd(vi)i-Bu i-Bu fb(vii) sec-Bu H fc(vii) H sec-Bu fd(vii) sec-Bu sec-Bufb(viii) tert-Bu H fc(viii) H tert-Bu fd(viii) tert-Bu tert-Bu fe(ix)

fe(x)

fe(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table G of Lower Chains B R⁴ R⁵ R⁶ ga gb(i) gc(i) gd(i) H Me H Me H H MeMe

gb(ii) Et H gc(ii) H Et gd(ii) Et Et gb(iii) n-Pr H gc(iii) H n-Prgd(iii) n-Pr n-Pr gb(iv) i-Pr H gc(iv) H i-Pr gd(iv) i-Pr i-Pr gb(v)n-Bu H gc(v) H n-Bu gd(v) n-Bu n-Bu gb(vi) i-Bu H gc(vi) H i-Bu gd(vi)i-Bu i-Bu gb(vii) sec-Bu H gc(vii) H sec-Bu gd(vii) sec-Bu sec-Bugb(viii) tert-Bu H gc(viii) H tert-Bu gd(viii) tert-Bu tert-Bu ge(ix)

ge(x)

ge(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table H of Lower Chains B R⁴ R⁵ R⁶ ha hb(i) hc(i) hd(i) H Me H Me H H MeMe

hb(ii) Et H hc(ii) H Et hd(ii) Et Et hb(iii) n-Pr H hc(iii) H n-Prhd(iii) n-Pr n-Pr hb(iv) i-Pr H hc(iv) H i-Pr hd(iv) i-Pr i-Pr hb(v)n-Bu H hc(v) H n-Bu hd(v) n-Bu n-Bu hb(vi) i-Bu H hc(vi) H i-Bu hd(vi)i-Bu i-Bu hb(vii) sec-Bu H hc(vii) H sec-Bu hd(vii) sec-Bu sec-Buhb(viii) tert-Bu H hc(viii) H tert-Bu hd(viii) tert-Bu tert-Bu he(ix)

he(x)

he(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table I of Lower Chains B R⁴ R⁵ R⁶ ia ib(i) ic(i) id(i) H Me H Me H H MeMe

ib(ii) Et H ic(ii) H Et id(ii) Et Et ib(iii) n-Pr H ic(iii) H n-Prid(iii) n-Pr n-Pr ib(iv) i-Pr H ic(iv) H i-Pr id(iv) i-Pr i-Pr ib(v)n-Bu H ic(v) H n-Bu id(v) n-Bu n-Bu ib(vi) i-Bu H ic(vi) H i-Bu id(vi)i-Bu i-Bu ib(vii) sec-Bu H ic(vii) H sec-Bu id(vii) sec-Bu sec-Buib(viii) tert-Bu H ic(viii) H tert-Bu id(viii) tert-Bu tert-Bu ie(ix)

ie(x)

ie(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table J of Lower Chains B R⁴ R⁵ R⁶ ja jb(i) jc(i) jd(i) H Me H Me H H MeMe

jb(ii) Et H jc(ii) H Et jd(ii) Et Et jb(iii) n-Pr H jc(iii) H n-Prjd(iii) n-Pr n-Pr jb(iv) i-Pr H jc(iv) H i-Pr jd(iv) i-Pr i-Pr jb(v)n-Bu H jc(v) H n-Bu jd(v) n-Bu n-Bu jb(vi) i-Bu H jc(vi) H i-Bu jd(vi)i-Bu i-Bu jb(vii) sec-Bu H jc(vii) H sec-Bu jd(vii) sec-Bu sec-Bujb(viii) tert-Bu H jc(viii) H tert-Bu jd(viii) tert-Bu tert-Bu je(ix)

je(x)

je(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (ii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table K of Lower Chains B R⁴ R⁵ R⁶ ka kb(i) kc(i) kd(i) H Me H Me H H MeMe

kb(ii) Et H kc(ii) H Et kd(ii) Et Et kb(iii) n-Pr H kc(iii) H n-Prkd(iii) n-Pr n-Pr kb(iv) i-Pr H kc(iv) H i-Pr kd(iv) i-Pr i-Pr kb(v)n-Bu H kc(v) H n-Bu kd(v) n-Bu n-Bu kb(vi) i-Bu H kc(vi) H i-Bu kd(vi)i-Bu i-Bu kb(vii) sec-Bu H kc(vii) H sec-Bu kd(vii) sec-Bu sec-Bukb(viii) tert-Bu H kc(viii) H tert-Bu kd(viii) tert-Bu tert-Bu ke(ix)

ke(x)

ke(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table L of Lower Chains B R⁴ R⁵ R⁶ la lb(i) lc(i) ld(i) H Me H Me H H MeMe

lb(ii) Et H lc(ii) H Et ld(ii) Et Et lb(iii) n-Pr H lc(iii) H n-Prld(iii) n-Pr n-Pr lb(iv) i-Pr H lc(iv) H i-Pr ld(iv) i-Pr i-Pr lb(v)n-Bu H lc(v) H n-Bu ld(v) n-Bu n-Bu lb(vi) i-Bu H lc(vi) H i-Bu ld(vi)i-Bu i-Bu lb(vii) sec-Bu H lc(vii) H sec-Bu ld(vii) sec-Bu sec-Bulb(viii) tert-Bu H lc(viii) H tert-Bu ld(viii) tert-Bu tert-Bu le(ix)

le(x)

le(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table M of Lower Chains B R⁴ R⁵ R⁶ ma mb(i) mc(i) md(i) H Me H Me H H MeMe

mb(ii) Et H mc(ii) H Et md(ii) Et Et mb(iii) n-Pr H mc(iii) H n-Prmd(iii) n-Pr n-Pr mb(iv) i-Pr H mc(iv) H i-Pr md(iv) i-Pr i-Pr mb(v)n-Bu H mc(v) H n-Bu md(v) n-Bu n-Bu mb(vi) i-Bu H mc(vi) H i-Bu md(vi)i-Bu i-Bu mb(vii) sec-Bu H mc(vii) H sec-Bu md(vii) sec-Bu sec-Bumb(viii) tert-Bu H mc(viii) H tert-Bu md(viii) tert-Bu tert-Bu me(ix)

me(x)

me(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table N of Lower Chains B R⁴ R⁵ R⁶ na nb(i) nc(i) nd(i) H Me H Me H H MeMe

nb(ii) Et H nc(ii) H Et nd(ii) Et Et nb(iii) n-Pr H nc(iii) H n-Prnd(iii) n-Pr n-Pr nb(iv) i-Pr H nc(iv) H i-Pr nd(iv) i-Pr i-Pr nb(v)n-Bu H nc(v) H n-Bu nd(v) n-Bu n-Bu nb(vi) i-Bu H nc(vi) H i-Bu nd(vi)i-Bu i-Bu nb(vii) sec-Bu H nc(vii) H sec-Bu nd(vii) sec-Bu sec-Bunb(viii) tert-Bu H nc(viii) H tert-Bu nd(viii) tert-Bu tert-Bu ne(ix)

ne(x)

ne(xi)

R⁴ and/or R⁵ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R⁴ and R⁵ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table O of Lower Chains B R⁴ R⁵ R⁶ oa ob(i) oc(i) od(i) H Me H Me H H MeMe

ob(ii) Et H oc(ii) H Et od(ii) Et Et ob(iii) n-Pr H oc(iii) H n-Prod(iii) n-Pr n-Pr ob(iv) i-Pr H oc(iv) H i-Pr od(iv) i-Pr i-Pr ob(v)n-Bu H oc(v) H n-Bu od(v) n-Bu n-Bu ob(vi) i-Bu H oc(vi) H i-Bu od(vi)i-Bu i-Bu ob(vii) sec-Bu H oc(vii) H sec-Bu od(vii) sec-Bu sec-Buob(viii) sec-bu H oc(viii) H tert-Bu od(viii) tert-Bu tert-Bu oe(ix)

oe(x)

oe(xi)

R₄ and/or R₅ = C₁-C₄ alkyl* (i) Me (ii) Et (iii) n-Pr (iv) i-Pr (v) n-Bu(vi) i-Bu (vii) sec-Bu (viii) tert-Bu

(ix) cyclopropyl (x) cyclobutyl (xi) cyclopentyl *R₄ and R₅ may both beC₁-C₄ alkyl groups that are not the same. Although no examples of theseembodiments are represented in these tables, their absence infers nolimitation in scope.

Table P/Q of Lower Chains B p

q

(±)-Dimethyl (3-methyl-2-oxohept-5-yn-1-yl)phosphonate (15ab(i)/15ac(i))

Scheme 7a, Step A: Preparation of diethyl2-(but-2-yn-1-yl)-2-methylmalonate

To a stirring mixture consisting of diethyl 2-methylmalonate(Sigma-Aldrich, 34.8 g, 200 mmol) in THF (50 mL) at −78° C. was addedlithium bis-(trimethylsilyl)amide (1M in THF, 200 mL, 200 mmol) and theresulting reaction mixture was stirred at −78° C. for 30 minutes. To thereaction mixture was added a mixture consisting of 1-bromobut-2-yne(GFS, 25 g, 190 mmol) in THF (50 mL), and the mixture was stirred foranother hour at −78° C., and was then allowed to warm to roomtemperature. The mixture was treated with 10% aqueous sodium hydrogensulfate, diluted with brine (800 mL), and extracted with ethyl acetate(300 mL). The organic phase was washed with brine (2×250 mL), dried oversodium sulfate, filtered, and concentrated. The residue (brown oil) waspurified by silica gel chromatography. Elution with ethyl acetate-hexane(1:9 v/v) afforded the title intermediate (41.5 g, 97.6%); TLC R_(f)0.52 (solvent system: 1:9 v/v ethyl acetate-hexane).

Scheme 7a, Step B: Preparation of (±)-ethyl 2-methylhex-4-ynoate(14ab(i)/14ac(i))

To a mixture consisting of diethyl-2-(but-2-yn-1-yl)-methylmalonate(41.5 g, 184 mmol) in DMSO (150 mL) was added lithium chloride (8.05 g,190 mmol) and water (6.2 mL), and the stirring mixture was heated at160° C. overnight. The reaction mixture was cooled and diluted withbrine, and the organic material was extracted with ethyl acetate (250mL). The organic phase was washed with brine (2×200 mL), dried oversodium sulfate, filtered, and concentrated. The residue (dark brown oil)was filtered through a pad of silica gel, using ethyl acetate-hexane(1:4 v/v) to flush the column. The filtrate was concentrated to give thetitle intermediate (22.3 g, 78.9%) as a colorless oil; TLC R_(f) 0.37(solvent system: 1:4 v/v ethyl acetate:hexanes).

Scheme 8, Step A: Preparation of (±)-dimethyl(3-methyl-2-oxohept-5-yn-1-yl)phosphonate (15ab(i)/15ac(i))

To a stirring mixture consisting of dimethyl methylphosphonate (21.7 g,175 mmol) in THF (200 mL) at −78° C. was added n-butyllithium (1.6 M inhexanes, 106.2 mL, 169.9 mmol) and the mixture was allowed to continuestirring at −78° C. for one hour. To the reaction mixture was addeddropwise (±)-ethyl 2-methylhex-4-ynoate (22.3 g, 145 mmol) and theresulting mixture was stirred at −78° C. for three hours. The reactionmixture was treated with 10% sodium hydrogen sulfate to achieve pH 4,diluted with brine (800 mL), and extracted with ethyl acetate (250 mL).The organic phase was washed with brine (2×150 mL), dried over sodiumsulfate, filtered, and concentrated. The residue was purified by silicagel chromatography. Elution with ethyl acetate afforded the titleintermediate (24.12 g, 71.6%) as a colorless oil; TLC R_(f) 0.31(solvent system:ethyl acetate); MS (ESI⁺) m/z 233 (M+1).

Preparation of (S)-(+)-dimethyl(3-methyl-2-oxohept-5-yn-1-yl)phosphonate (15ab(i))

(S)-(+)-Dimethyl (3-methyl-2-oxohept-5-yn-1-yl)phosphonate was preparedin the same manner as that described for the preparation of intermediate15bb(i) except that intermediate (S)-2-methylhex-4-ynoic acid wasprepared instead of (S)-2-methylhept-4-ynoic acid and used to completethe synthesis of the title compound 15ab(i) as a clear oil; TLC R_(f)0.27 (solvent system: 4:1 v/v ethyl acetate-hexane); ¹H-NMR (CDCl₃) δ3.80 (s, 3H), 3.77 (s, 3H), 3.11-3.27 (m, 2H), 2.86-2.95 (m, 1H),2.23-2.42 (m, 2H), 1.71-1.77 (m, 3H), 1.18 (d, 3H); MS (ESI⁺) m/z 233(M+1); [α]²⁰ _(D)=+44° (c=1, CHCl₃).

Preparation of (±)-dimethyl (3-methyl-2-oxooct-5-yn-1-yl)phosphonate(15bb(i)/15bc(i))

(±)-Dimethyl (3-methyl-2-oxooct-5-yn-1-yl)phosphonate was prepared inthe same manner as that described for the preparation of intermediate15ab(i)/15ac(i) except that 1-bromopent-2-yne was used instead of1-bromobut-2-yne; chiral analytical HPLC (stationary phase: ChiralcelOJ-H normal phase 250×4.6 mm; mobile phase: 85:15 hexane/1-propanol;flow rate: 1 mL/min): two peaks each of essentially equal area, fastpeak having retention time of 5.8 min, slow peak having a retention timeof 6.5 min; MS (ESI⁺) m/z 247.1 (M+1).

Preparation of (S)-(+)-dimethyl (3-methyl-2-oxooct-5-yn-1-yl)phosphonate(15bb(i))

(S)-(+)-Dimethyl (3-methyl-2-oxooct-5-yn-1-yl)phosphonate was preparedby following the sequence of reaction steps described in Scheme 7a, 7fand Scheme 8, Step A. The intermediate 2-methylhept-4-ynoic acid wasprepared according to a method described in WO 2011/003058 A1.(S)-(+)-Diethyl (3-methyl-2-oxooct-5-yn-1-yl)phosphonate was preparedaccording to the method described in the Journal of Medicinal Chemistry,1986, 29(3), 313-315, except that 2,5-dioxopyrrolidin-1-yl2-methylhept-4-ynoate (N-hydroxysuccinimide 2-methylhept-4-ynoate) wasprepared as an activated acyl species (activated ester) instead of2-methylhept-4-ynoyl chloride to make the intermediate diastereomericpair N—((R)-2-hydroxy-1-phenylethyl)-2-methylhept-4-ynamide. Thediastereomers were separated by silica gel chromatography and thedesired diastereomer was manipulated as described to afford the titleintermediate as a clear oil. The absolute stereochemistry of the titleintermediate was proven by determination of its specific rotation.[α]^(T) _(λ)=α/cl, [α]^(21.9) _(D)=+0.574/(0.025 g/1 mL)(0.5)=+45.83°(c=1, CHCl₃). Literature reported specific rotation from Liebigs Annalender Chemie, 1989, 11, 1081-1083; [α]²⁰ _(D)=+37.7° (c=1, CHCl₃); chiralanalytical HPLC (stationary phase: Chiralcel OJ-H normal phase 250×4.6mm; mobile phase: 85:15 hexane/1-propanol; flow rate: 1 mL/min)retention time 6.4 min, 100% purity; TLC R_(f) 0.32 (solvent system: 4:1v/v ethyl acetate-hexane); ¹H-NMR (CDCl₃) δ 3.76-3.80 (m, 6H), 3.11-3.29(m, 2H), 2.86-2.95 (m, 1H), 2.36-2.44 (m, 1H), 2.26-2.33 (m, 1H),2.09-2.16 (m, 2H), 1.16-1.20 (m, 3H), 1.06-1.11 (m, 3H); MS (ESI⁺) m/z247 (M+1).

A second preparation of the title intermediate by the same processdescribed above afforded the title intermediate wherein the specificrotation (c=1, CHCl₃) is +49°.

Preparation of (±)-dimethyl (3-methyl-2-oxonon-5-yn-1-yl)phosphonate(15cb(i)/15 cc(i))

(±)-Dimethyl (3-methyl-2-oxonon-5-yn-1-yl)phosphonate was prepared inthe same manner as that described for the preparation of intermediate15ab(i)/15ac(i) except that 1-bromohex-2-yne (prepared from thecorresponding commercially available alcohol using PBr₃/pyridine) wasused instead of 1-bromobut-2-yne; MS (ESI⁺) m/z 261 (M+1).

Preparation of (S)-(+)-dimethyl (3-methyl-2-oxonon-5-yn-1-yl)phosphonate(15cb(i))

(S)-(+)-Dimethyl (3-methyl-2-oxonon-5-yn-1-yl)phosphonate was preparedin the same manner as that described for the preparation of intermediate15bb(i) except that intermediate (S)-2-methyloct-4-ynoic acid wasprepared instead of (S)-2-methylhept-4-ynoic acid and used to completethe synthesis of the title compound 15cb(i) as a clear oil; TLC R_(f)0.12 (solvent system: 3:2 v/v ethyl acetate-hexane); ¹H-NMR (CDCl₃) δ3.76-3.80 (m, 6H), 3.11-3.29 (m, 2H), 2.86-2.95 (m, 1H), 2.27-2.45 (m,2H), 2.04-2.12 (m, 2H), 1.39-1.55 (m, 2H), 1.13-1.24 (m, 3H), 0.94 (m,3H); MS (ESI⁺) m/z 261 (M+1); [α]²⁰ _(D)=+48.8° (c=1, CHCl₃).

Preparation of (±)-dimethyl(3-methyl-2-oxo-6-phenylhex-5-yn-1-yl)phosphonate (15db(i)/15dc(i))

(±)-Dimethyl (3-methyl-2-oxo-6-phenylhex-5-yn-1-yl)phosphonate wasprepared in the same manner as that described for the preparation ofintermediate 15ab(i)/15ac(i) except that (3-bromoprop-1-yn-1-yl)benzene(prepared from the corresponding commercially available alcohol usingPBr₃/pyridine) was used instead of 1-bromobut-2-yne to afford 2.4 g of aclear oil; ¹H-NMR (CDCl₃) δ 7.35-7.45 (m, 2H), 7.2-7.3 (m, 3H),3.85-3.75 (m, 6H), 3.25 (d, 2H), 3.0-3.2 (m, 1H), 2.5-2.7 (m, 2H), 1.25(d, 3H); MS (ESI⁺) m/z 295.1 (M+1).

Preparation of (S)-(+)-dimethyl(3-methyl-2-oxo-6-phenylhex-5-yn-1-yl)phosphonate (15db(i))

(S)-(+)-Dimethyl (3-methyl-2-oxo-6-phenylhex-5-yn-1-yl)phosphonate wasprepared in the same manner as that described for the preparation ofintermediate 15bb(i) except that intermediate(S)-2-methyl-5-phenylpent-4-ynoic acid was prepared instead of(S)-2-methylhept-4-ynoic acid and used to complete the synthesis of thetitle compound 15db(i) as a clear oil; TLC R_(f) 0.22 (solvent system:4:1 v/v ethyl acetate-hexane); MS (ESI⁺) m/z 295 (M+1).

Preparation of (±)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate(15mb(i)/15mc(i))

A mixture consisting of (±)-dimethyl(3-methyl-2-oxo-6-phenylhex-5-yn-1-yl)phosphonate (15db(i)/15dc(i)),(1.0 g, 3.4 mmol) and 10% palladium on activated carbon (15 mg) inmethanol (30 mL) was stirred under an atmosphere of hydrogen overnight.The hydrogen was evacuated and the mixture was filtered through amicropore filter. The filtrate was concentrated in vacuo to afford thetitle compound (1.0 g, quantitative yield) as a clear oil; ¹H-NMR(CDCl₃) δ 7.3-7.25 (m, 2H), 7.2-7.1 (m, 3H), 3.8-3.7 (m, 6H), 3.1 (d,2H), 2.8-2.75 (m, 1H), 2.7-2.5 (m, 2H), 1.8-1.65 (m, 1H), 1.65-1.5 (m,2H), 1.4-1.3 (m, 1H), 1.1 (d, 3H); MS (ESI⁻) m/z 299 (M+1).

Preparation of (S)-(+)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i))

(S)-(+)-Dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate was preparedas a clear oil in the same manner as that described for the preparationof phosphonate 15mb(i)/15mc(i); ¹H-NMR (CDCl₃) δ 7.3-7.2 (m, 2H),7.2-7.1 (m, 3H), 3.8-3.7 (m, 6H), 3.12 (s, 1H), 3.07 (s, 1H), 2.8-2.7(m, 1H), 2.7-2.5 (m, 2H), 1.8-1.7 (m, 2H), 1.7-1.5 (m, 2H), 1.1 (d, 3H);MS (ESI⁺) m/z 299 (M+1).

Alternative preparation of (S)-(+)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i))

Scheme 7f, Step A: Preparation of (±)-2-methyl-5-phenylpentanoic acid(20mb(i)/20mc(i))

To a solution consisting of diisopropylamine (218.25 mL, 1557.3 mmol) inTHF (400 mL) at −50° C. was added an n-butyllithium solution (628 mL,393 mmol, 1.6 M solution in hexane). The reaction mixture was stirredfor five minutes and was then allowed to warm to −20° C. To the reactionmixture was added dropwise a solution consisting of propionic acid(44.67 g, 603 mmol) in HMPA (102 mL). The reaction mixture was stirredat room temperature for 30 minutes, and subsequently cooled to 0° C.,after which a mixture consisting of 1-bromo-3-phenylpropane (100 g, 502mmol) in THF (200 mL) was added. The resulting reaction mixture stirredat room temperature for two hours. The reaction mixture was diluted withwater and extracted with ethyl acetate. The aqueous layer was separatedand then acidified with 2 M HCl until acidic. The aqueous layer was thenextracted three times with ethyl acetate, and the organic layers werecombined and dried over sodium sulfate, filtered, and concentrated toafford the title intermediate (105 g, quantitative yield) as a clearoil; TLC R_(f) 0.44 (solvent system: 25:75:1 v/v/v ethylacetate-heptane-acetic acid.

Scheme 7f, Step B: Preparation of (±)-2,5-dioxopyrrolidin-1-yl2-methyl-5-phenylpentanoate (18mb(i))

To a mixture consisting of (±)-2-methyl-5-phenylpentanoic acid(20mb(i)/20mc(i), 105.6 g, 549.1 mmol) in dichloromethane (800 mL) wasadded N-hydroxysuccinimide (69.5 g, 604 mmol), 4-dimethylaminopyridine(73.8 g, 604 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimidehydrochloride (115.8 g, 604.0 mmol) and the reaction mixture was stirredovernight at room temperature. The reaction mixture was extracted withdichloromethane and washed twice with brine, dried over sodium sulfate,filtered, and concentrated under vacuum. The residue was purified bysilica gel chromatography. Elution with ethyl acetate-heptane (30:70v/v) afforded the title intermediate (85.6 g, 54%); TLC R_(f) 0.32(solvent system 25:75 v/v ethyl acetate-heptane.

Scheme 7f, Steps C and D: Preparation of(S)—N—((R)-2-hydroxy-1-phenylethyl)-2-methyl-5-phenylpentanamide(19mb(i))

To a solution consisting of (±)-2,5-dioxopyrrolidin-1-yl2-methyl-5-phenyl pentanoate (18mb(i), 85.6 g, 296 mmol) in THF (3000mL) at 48° C. was added R-(−)-2-phenylglycinol (65.9 g, 480 mmol, BridgeOrganics) in portions. The resulting reaction mixture was stirred at 48°C. for 40 hours. A white precipitate formed, which was filtered from thereaction mixture and washed with THF. The filtrate was concentratedunder vacuum and the residue, comprising the diastereomeric pair, waschromatographed on silica gel. Elution with ethyl acetate-heptane (50:50v/v) afforded the pure diastereomer title compound (31.3 g, 34%) as acolorless solid; TLC R_(f) 0.205 (solvent system: 50:50 v/v ethylacetate-heptane); HPLC retention time 15.1 minutes, stationary phase:Gemini 5μ C18 250×4.6 mm, ultraviolet detector at 210 nm, mobile phase:1 mL/min, 60:40:0.1 v/v methanol-water-acetic acid.

Scheme 7f, Step E1: Preparation of(S)-(+)-2-methyl-5-phenylpentanoicacid (20mb(i))

To a solution consisting of(S)—N—((R)-2-hydroxy-1-phenylethyl)-2-methyl-5-phenylpentanamide(19mb(i), 3.5 g, 11.24 mmol) in 1,4-dioxane (80 mL) was added aqueoussulfuric acid (36 mL, 3 N solution) and the mixture was stirredovernight at 80° C. The reaction mixture was extracted with ethylacetate three times and the organic layers were combined, dried oversodium sulfate, filtered, and concentrated under vacuum. The residue waspurified by silica gel chromatography. Elution with ethylacetate-heptane-acetic acid (30:70:0.4 v/v/v) afforded the titlecompound (2.4 g, quantitative yield) as a clear oil; R_(f) 0.48 (solventsystem: 30:70:0.4 v/v/v ethyl acetate-heptane-acetic acid; HPLCretention time 26.0 minutes; Chiralpak IA, 5μ, 4.6×25 mm, ultravioletdetector at 208 nm 0.75 ml/min 99:1:0.5 v/v heptanes-2-propanol-aceticacid; MS (ESI⁻) m/z 191.1 (M−H)⁻; ¹H-NMR (CDCl₃) δ 7.33-7.27 (m, 2H),7.22-7.16 (m, 3H), 2.67-2.60 (m, 2H), 2.56-2.46 (m, 1H), 1.80-1.60 (m,3H), 1.59-1.36 (m, 1H), 1.25-1.14 (m, 3H); [α]^(T) _(λ)=α/cl, [α]^(21.9)_(D)=+0.089/(0.01501 g/1.5 mL)(0.5)=+17.79° (c=1, CHCl₃).

Scheme 7f, Step F1: Preparation of (S)-(+)-ethyl2-methyl-5-phenylpentanoate (14mb(i))

To a solution consisting of (S)-(+)-2-methyl-5-phenylpentanoic acid(20mb(i), 2.3 g, 12 mmol) in ethanol (200 mL) was added 4 drops ofconcentrated sulfuric acid. The stirring reaction mixture was brought toreflux overnight and was subsequently cooled and concentrated undervacuum. The residue was diluted with ethyl acetate and washed twice withbrine. The organic layer was dried over sodium sulfate, filtered, andconcentrated under vacuum to afford the title compound (2.4 g, 91%) as aclear oil; TLC R_(f) 0.66 (solvent system: 15:85:1 v/v/v ethylacetate-heptane-acetic; MS (ESI⁺) m/z 221.2 (M+H)⁺; ¹H-NMR (CDCl₃) δ7.29-7.25 (m, 2H), 7.21-7.13 (m, 3H), 4.12 (q, J=6.96 Hz, 2H), 2.64-2.57(m, 2H), 2.48-2.39 (m, 1H), 1.75-1.54 (m, 3H), 1.52-1.41 (m, 1H), 1.24(t, J=7.14 Hz, 3H) 1.16-1.11 (m, 3H); [α]^(T) _(λ)=α/cl, [α]^(21.9)_(D)=+0.101/(0.01506 g/1.5 ml)(0.5)=+20.12° (c=1, CHCl₃).

Scheme 6: Preparation of (S)-(+)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i))

To a stirring solution consisting of dimethyl methylphosphonate (23.37g, 188.4 mmol) in THF (400 mL) at −78° C. was slowly addedn-butyllithium solution (112 mL, 179 mmol, 1.6 M solution in hexane).The reaction mixture was stirred for 30 minutes, after which time,(S)-(+)-ethyl 2-methyl-5-phenylpentanoate (14mb(i), 28.1 g, 94.2 mmol)in THF (100 mL) was slowly added. The resulting reaction mixture wasstirred at −78° C. for two hours and was then allowed to rise to roomtemperature overnight. The reaction mixture was treated with 5% KHSO₄and extracted with ethyl acetate three times. The organic layer waswashed twice with 50:50 water-brine and the organic layer was dried oversodium sulfate, filtered, and concentrated under vacuum. The residue waspurified by silica gel chromatography. Elution with ethylacetate-heptane (60:40 v/v) afforded the title compound (11.9 g, 42%) asa clear oil, pure of unrelated components; TLC R_(f) 0.22 (solventsystem: 60:40 v/v ethyl acetate-heptane); HPLC retention time 14.5minutes, 5μ Chiralpak IA 250×4.6 mm, ultraviolet detector at 210 nm, 1mL/min, chiral purity 97.8% (S), 2.19% (R); MS (ESI⁻) m/z 297.1 (M−H)⁻;¹H NMR (CDCl₃) δ 7.28-7.21 (m, 2H), 7.17-7.12 (m, 3H), 3.76-3.71 (m,6H), 3.10 (d, J=2.20 Hz, 1H), 3.04 (d, J=2.20 Hz, 1H), 2.79-2.70 (m,1H), 2.54-2.62 (m, 2H), 1.74-1.54 (m, 3H), 1.42-1.24 (m, 1H), 1.07 (d,J=6.96 Hz, 3H); [α]^(T) _(λ)=α/cl, [α]^(21.9) _(D)=+0.084/(0.0169 g/1.5mL)(0.5)=+14.91° (c=1.13, CHCl₃).

The chromatography also provided additional title compound (8.3 g) withapproximately 95% chemical purity based on visual observation of TLC;chiral purity 98.19% (S), 1.81% (R).

Second alternative preparation of (S)-(+)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i))

Scheme 7g, Step B: Preparation of(S)-4-benzyl-3-(5-phenylpentanoyl)oxazolidin-2-one (21ma)

To a stirring solution consisting of (S)-4-benzyloxazolidin-2-one (0.9g, 5.08 mmol) in THF (20 mL) at −78° C. was slowly added n-butyllithiumsolution (3.5 mL, 5.6 mmol, 1.6 M solution in hexane). The reactionmixture was stirred at −78° C. for two hours, after which time5-phenylpentanoyl chloride (1 g, 5 mmol, prepared by treatment of5-phenylpentanoic acid with oxalyl chloride and catalytic DMF) wasslowly added. The reaction mixture was stirred at −78° C. for two hoursand was then allowed to rise to room temperature overnight. The reactionmixture was acidified with 5% KHSO₄ and extracted twice with ethylacetate. The organic phase was washed with brine, dried over sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified by silica gel chromatography. Elution with ethylacetate-heptane (25:75 v/v) afforded the title compound (1.4 g, 82%) asa clear oil; TLC R_(f) 0.40 (solvent system: 25:75 v/v ethylacetate-heptane); MS (ESI⁺) m/z 337.4 (M+H)⁺, 360.2 (M+Na)⁺.

Scheme 7g, Step C: Preparation of(S)-4-benzyl-3-((S)-2-methyl-5-phenylpentanoyl)oxazolidin-2-one(21mb(i))

To a stirring solution consisting of(S)-4-benzyl-3-(5-phenylpentanoyl)oxazolidin-2-one (21ma, 1.24 g, 3.68mmol) in THF (20 mL) at −78° C. was slowly added lithiumbis-(trimethylsilyl)amide solution (4.41 mL, 4.41 mmol, 1 M solution inTHF). The reaction mixture was stirred at −78° C. for one hour, afterwhich time iodomethane (0.27 mL, 4.2 mmol) was slowly added. Theresulting reaction mixture was allowed to rise to room temperature withstirring overnight. The mixture was acidified with 5% KHSO₄ andextracted twice with ethyl acetate. The organic layer was washed twicewith brine, dried over sodium sulfate, filtered, and concentrated undervacuum. The residue was purified by silica gel chromatography. Elutionwith ethyl acetate-heptane (25:75 v/v) afforded the title compound (563mg, 43.6%) as a clear oil; TLC R_(f) 0.53 (solvent system: 25:75 v/vethyl acetate-heptane; MS (ESI⁺) m/z 352.3 (M+H)⁺374.2 (M+Na)⁺.

Scheme 7g, Step D: Preparation of (S)-2-methyl-5-phenylpentanoic acid(20mb(i))

To a stirring aqueous mixture cooled to 0° C. comprising(S)-4-benzyl-3-((S)-2-methyl-5-phenylpentanoyl)oxazolidin-2-one(21mb(i), 563 mg, 1.60 mmol) was added hydrogen peroxide and lithiumhydroxide. The resulting reaction mixture was stirred for four hours.The reaction mixture was acidified with 5% KHSO₄ and extracted twicewith ethyl acetate, the organic layer was washed twice with brine, driedover sodium sulfate, and concentrated under vacuum. The residue waspurified by silica gel chromatography. Elution with ethylacetate-heptane-acetic acid (25:75:0.4) afforded the title compound (293mg, 95%) as a colorless oil; TLC R_(f) 0.35 (solvent system: 25:75:0.4v/v/v ethyl acetate-heptane-acetic acid); HPLC retention time 12.08 min,stationary phase: Chiralpak IA 4.6×25 mm 5μ, ultraviolet detector at 210nm, mobile phase: 1 mL/min 99:1:0.1 heptane: 2-propanol:acetic acid,97.22% (S), 2.78% (R).

Scheme 7g, Step E: Preparation of (S)-2,5-dioxopyrrolidin-1-yl2-methyl-5-phenylpentanoate (18mb(i))

To a mixture consisting of (S)-2-methyl-5-phenylpentanoic acid (20mb(i),290 mg, 1.51 mmol) in dichloromethane (20 mL) was addedN-hydroxysuccinimide (191 mg, 1.66 mmol), 4-dimethylaminopyridine (203mg, 1.66 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimidehydrochloride (318 mg, 1.66 mmol). The resulting reaction mixture wasstirred for two hours at room temperature. The reaction mixturecomprising 18mb(i) was carried on directly to the next step.

Scheme 7g, Step F and G: Preparation of(S)—N—((R)-2-hydroxy-1-phenylethyl)-2-methyl-5-phenylpentanamide(19mb(i))

To the reaction mixture comprising 18mb(i) prepared as described abovewas added R-(−)-2-phenylglycinol, and the resulting reaction mixture wasstirred overnight. The mixture was filtered and washed with THF. Thecombined filtrate and THF wash was concentrated under vacuum. Theresidue was purified by silica gel chromatography. Elution with ethylacetate-heptane (60:40 v/v) provided a solid, which was crystallizedfrom ethyl acetate-heptane to afford the highly-stereopure titlecompound (198 mg, 42%) as a white solid; TLC R_(f) 0.21 (solvent system:60:40 v/v ethyl acetate-heptane; HPLC retention time 14.68 minutes,stationary phase: Gemini, 5μ C18 250×4.6 mm, ultraviolet wavelength of210 nm, mobile phase: 1 mL/min, 60:40:0.1 methanol-water-acetic acid,100% (S); MS (ESI⁺) m/z 312.2 (M+H)⁺, 334.1 (M+Na)⁺.

Preparation of (S)-(+)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i))

(S)-(+)-Dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) isprepared in three steps from the highly stereopure(S)—N—((R)-2-hydroxy-1-phenylethyl)-2-methyl-5-phenylpentanamide(19mb(i)) prepared by the Scheme 7g route as it is from the 19mb(i)derived from the reaction sequence of Scheme 7f starting from(±)-2-methyl-5-phenylpentanoic acid (20mb(i)/20mc(i)).

Preparation of (R)-(−)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mc(i))

Preparation of(−)-(R)—N—((R)-2-hydroxy-1-phenylethyl)-2-methyl-5-phenylpentanamide(19mc(i))

(−)-(R)—N—((R)-2-Hydroxy-1-phenylethyl)-2-methyl-5-phenylpentanamide wasprepared from (±)-2-methyl-5-phenylpentanoic acid (20mb(i)/20mc(i)) inthe same manner as(S)—N—((R)-2-hydroxy-1-phenylethyl)-2-methyl-5-phenylpentanamide(19mb(i)) described above. Silica gel chromatography provided separationof the title compound from its diastereomer (19mb(i)) to provide thedesired product (30.2 g, 33%) as a white solid; TLC R_(f) 0.33 (solventsystem: 50:50 v/v ethyl acetate-heptane); HPLC retention time 13.25minutes, Gemini 5μ C18 250×4.6 mm, at ultraviolet wavelength of 210 nm,1 mL/min, 60:40:0.1 methanol-water-acetic acid, purity 99.36% (R), 0.64%(S); [α]^(T) _(λ)=α/cl, [α]^(21.9) _(D)=−0.066/(0.01573 g/2mL)(0.5)=−16.78° (c=0.7865, CHCl₃).

Preparation of (R)-(−)-2-methyl-5-phenylpentanoic acid (20mc(i))

R)-(−)-2-Methyl-5-phenylpentanoic acid was prepared from 19mc(i) (30 g)in the same manner (S)-(+)-2-methyl-5-phenylpentanoic acid was preparedfrom 19mb(i) as described above. The residue was purified by silica gelchromatography. Elution with ethyl acetate-heptane-acetic acid(20:80:0.4 v/v/v) afforded the title compound (20.8 g) as a clear oil;TLC R_(f) 0.51 (solvent system: 30:70:1 v/v/v ethylaceate-hepatane-acetic acid; HPLC retention time 24.46 min; Chiralpak IA4.6×25 mm 5μ, at a wavelength of 208 nm 0.75 mL/min, 99:1:0.5 heptane:2-propanol:acetic acid, chiral purity 99.32% (R), 0.68% (S); MS (ESI⁻)m/z 191.1 (M−H)⁻; ¹H-NMR (CDCl₃) δ 7.31-7.26 (m, 2H), 7.21-7.15 (m, 3H),2.67-2.57 (m, 2H), 2.54-2.44 (m, 1H), 1.79-1.59 (m, 3H) 1.58-1.41 (m,1H), 1.18 (d, J=6.96 Hz, 3H).

Preparation of (R)-(−)-ethyl 2-methyl-5-phenylpentanoate (14mc(i))

(R)-(−)-Ethyl 2-methyl-5-phenylpentanoate was prepared from 20mc(i)(20.8 g) in the same manner (S)-(+)-ethyl 2-methyl-5-phenylpentanoatewas prepared from 20mb(i) as described above. The residue was purifiedby silica gel chromatography. Elution with ethyl acetate-heptane (5:95v/v) afforded the title compound (21.0 g, 88%) as a clear oil; TLC R_(f)0.66 (solvent system: 15:85:1 v/v/v ethyl acetate-heptane-acetic acid);MS (ESI⁺) m/z 221.2 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.32-7.26 (m, 2H),7.20-7.14 (m, 3H), 4.11 (q, J=7.32 Hz, 2H), 2.64-2.57 (m, 2H), 2.48-2.39(m, 1H), 1.75-1.53 (m, 3H), 1.52-1.41 (m, 1H), 1.27-1.21 (m, 3H), 1.13(d, J=6.96 Hz, 3H,); [α]^(T) _(λ)=α/cl, [α]^(21.9) _(D)=−0.114/(0.01771g/1.5 mL)(0.5)=−19.31° (c=1.18, CHCl₃).

Preparation of (R)-(−)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mc(i))

(R)-(−)-Dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate was preparedfrom 14mc(i) (93 mg) in the same manner (S)-(+)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate was prepared from 14mb(i) asdescribed above. The residue was purified by silica gel chromatography.Elution with ethyl acetate-heptane (70:30 v/v) afforded the titlecompound (83 mg, 66%) as a colorless oil; TLC R_(f) 0.22 (solventsystem: 70:30 v/v ethyl acetate-heptane); HPLC retention time 12.36 min,5μ Chiralpak OJ-H 4.6×250 mm, at ultraviolet wavelength of 210 nm,90:10:0.1 heptane-ethanol:acetic acid) 1 mL/min, chiral purity 100% (R);MS (ESI⁻) m/z 297.1 (M−H)⁻; ¹H NMR (CDCl₃) δ 7.29 (d, J=6.51 Hz, 2H,),7.22-7.16 (m, 3H), 3.77 (d, J=11.35 Hz, 3H), 3.78 (d, J=11.35 Hz, 3H),3.13 (d, J=1.83 Hz, 1H), 3.08 (d, J=1.83 Hz, 1H), 2.78 (d, J=6.96 Hz,1H), 2.67-2.56 (m, 2H), 1.61-1.52 (m, 3H), 1.45-1.32 (m, 1H), 1.11 (d,J=6.96 Hz, 3H); [α]^(T) _(λ)=α/cl, [α]^(21.9) _(D)=−0.080/(0.01742 g/1.5mL)(0.5)=−13.78° (c=1.16, CHCl₃).

Dimethyl (2-oxohept-5-yn-1-yl)phosphonate (15aa)

Scheme 7a, Step A: Preparation of diethyl 2-(but-2-yn-1-yl)malonate(16a)

To a stirring mixture consisting of diethyl malonate (24.3 g, 141 mmol)in THF (140 mL) was added sodium hydride (60% dispersion in oil, 2.8 g,70 mmol) and the resulting reaction mixture was stirred for 50 minutes.To the reaction mixture was added 1-bromobut-2-yne (GFS, 6.2 g, 47mmol), and the mixture was stirred for two hours. The reaction mixturewas treated carefully with 0.5 N HCl and extracted with ethyl acetate.The organic phase was washed with water, then brine, dried overmagnesium sulfate, filtered, and concentrated. The residue was purifiedby silica gel chromatography. Elution with ethyl acetate-heptane (5:95to 15:85 v/v) afforded the title intermediate (11.5 g, quantitativeyield) as a clear oil.

Preparation of dimethyl (2-oxohept-5-yn-1-yl)phosphonate (15aa)

Dimethyl (2-oxohept-5-yn-1-yl)phosphonate was prepared in two steps fromdiethyl 2-(but-2-yn-1-yl)malonate in the same manner as that describedfor intermediate 15ab(i)/15ac(i) to afford the title phosphonateintermediate (2.5 g) as a clear oil; ¹H-NMR (CDCl₃) 3.78 (d, 6H, J=11.5Hz), 3.1 (d, 2H, J=22.5 Hz), 2.80 (t, 2H), 2.42-2.35 (m, 2H), 1.73 (t,3H).

Preparation of dimethyl (2-oxooct-5-yn-1-yl)phosphonate (15ba)

Dimethyl (2-oxooct-5-yn-1-yl)phosphonate was prepared in the same manneras that described for the preparation of intermediate 15aa except that1-bromopent-2-yne (GFS, 6.9 g, 47 mmol) was used instead of1-bromobut-2-yne to afford the title phosphonate intermediate (4.0 g) asa clear oil; ¹H-NMR (CDCl₃) δ 3.78 (d, 6H, J=11.1 Hz), 3.11 (d, 2H,J=22.8 Hz), 2.81 (t, 2H), 2.45-2.38 (m, 2H), 2.28-2.36 (m, 2H), 1.08 (t,3H).

Preparation of dimethyl (2-oxonon-5-yn-1-yl)phosphonate (15ca)

Dimethyl (2-oxonon-5-yn-1-yl)phosphonate is prepared in the same manneras that described for the preparation of intermediate 15aa except that1-bromohex-2-yne is used instead of 1-bromobut-2-yne.

Preparation of dimethyl (2-oxo-6-phenylhex-5-yn-1-yl)phosphonate (15da)

Scheme 7a, Step A: Preparation of diethyl 2-(hex-2-yn-1-yl)malonate(16d)

To a stirring suspension consisting of sodium hydride (1.22 g, 51.3mmol) in THF (100 mL) at 0° C. was added dropwise a solution consistingof diethyl malonate (12.3 g, 76.9 mmol) in THF (20 mL) and the reactionmixture was stirred for 30 minutes. To the 0° C. reaction mixture wasadded a solution consisting of (3-bromoprop-1-yn-1-yl)benzene (5.0 g, 26mmol, prepared from the corresponding commercially available alcoholusing PBr₃/pyridine) in THF (30 mL) and the mixture was allowed to warmto room temperature for one hour. The reaction mixture was quenched withan aqueous solution of sodium chloride (500 mL) and extracted withdiethyl ether (500 mL). The organic phase was washed with brine (300mL), dried over sodium sulfate, filtered, and concentrated to afford thetitle intermediate (10.6 g) which was used as is in the next stepimmediately below; TLC R_(f) 0.47 (solvent system: 1:5 v/v ethylacetate-heptane).

Preparation of dimethyl (2-oxo-6-phenylhex-5-yn-1-yl)phosphonate (15da)

Dimethyl (2-oxo-6-phenylhex-5-yn-1-yl)phosphonate was prepared in twosteps from diethyl 2-(hex-2-yn-1-yl)malonate in the same manner as thatdescribed for the preparation of intermediate 15ab(i)/15ac(i) to afford2.12 g; TLC R_(f) 0.22 (solvent system: 4:1 v/v ethyl acetate-heptane);¹H-NMR (CDCl₃) δ 7.31-7.41 (m, 2H), 6.68-7.28 (m, 3H), 3.76-3.81 (m,6H), 3.17 (s, 1H), 3.12 (s, 1H), 2.92-2.98 (m, 2H), 2.65-2.71 (m, 2H);MS (ESI⁺) m/z 281 (M+1).

Preparation of dimethyl (2-oxo-6-phenylhexyl)phosphonate (15ma)

Dimethyl (2-oxo-6-phenylhexyl)phosphonate was prepared in the samemanner as that described for the preparation of intermediate15ab(i)/15ac(i) except that methyl 5-phenylpentanoate (Sigma-Aldrich)was used instead of (±)-ethyl 2-methylhex-4-ynoate; ¹H-NMR (CDCl₃) δ7.29-7.23 (m, 2H), 7.19-7.13 (m, 3H), 3.76 (d, 6H, J=11.1 Hz), 3.06 (d,2H, J=22.6 Hz), 2.55-2.7 (m, 4H), 1.55-1.7 (m, 4H).

Scheme 6: Preparation of dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate(15hd(i))

Dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate was prepared in the samemanner as that described for the preparation of intermediate15ab(i)/15ac(i) except that methyl 2,2-dimethylhexanoate (prepared bythe acid (p-toluenesulfonic acid) catalyzed esterification of2,2-dimethylhexanoic acid) was used instead of (±)-ethyl2-methylhex-4-ynoate; MS (ESI⁺) m/z 251 (M+1).

Scheme 6: Preparation of dimethyl (2-oxohex-3-yn-1-yl)phosphonate (15p)

Dimethyl (2-oxohex-3-yn-1-yl)phosphonate was prepared in the same manneras that described for the preparation of intermediate 15ab(i)/15ac(i)except that ethyl pent-2-ynoate was used instead of (±)-ethyl2-methylhex-4-ynoate; MS (ESI⁺) m/z 205 (M+1).

Scheme 6: Preparation of dimethyl(2-oxo-4-phenylbut-3-yn-1-yl)phosphonate (15q)

Dimethyl (2-oxo-4-phenylbut-3-yn-1-yl)phosphonate was prepared in thesame manner as that described for the preparation of intermediate15ab(i)/15ac(i) except that ethyl 3-phenylpropiolate was used instead of(±)-ethyl 2-methylhex-4-ynoate; MS (ESI⁺) m/z 253 (M+1).

(S)-dimethyl (2-oxo-3-phenylbutyl)phosphonate (15jb(i))

Preparation of (S)-ethyl 2-phenylpropanoate (15jb(i))

To a solution consisting of (S)-2-phenylpropanoic acid (1.0 g, 6.7 mmol,from Chem-Impex) in ethanol (30 mL) was added concentrated sulfuric acid(4 drops). The reaction mixture was stirred at reflux overnight in avessel equipped with a Dean-Stark condenser. To the mixture was addedsolid sodium bicarbonate and the resulting mixture was filtered andconcentrated under vacuum to afford the title compound (1.0 g, 84%) as acolorless oil; TLC R_(f) 0.5 (solvent system: 15:85:1 v/v/v ethylacetate-heptane-acetic acid). The product was carried directly onto thenext step without further purification.

Preparation of (S)-(+)-dimethyl (2-oxo-3-phenylbutyl)phosphonate(15jb(i))

To a stirring solution consisting of dimethyl methylphosphonate (1.392g, 11.22 mmol) in THF (20 mL) at −78° C. was slowly added n-butyllithiumsolution (6.6 mL, 11 mmol, 1.6 M solution in hexane). The mixture wasstirred for 30 minutes, after which time a mixture consisting of(S)-ethyl 2-phenylpropanoate (1.0 g, 5.6 mmol) in THF (10 mL) was slowlyadded, and the mixture stirred at −78° C. for two hours before beingallowed to rise to room temperature overnight. The reaction mixture wastreated with 5% aqueous KHSO₄ and extracted with ethyl acetate threetimes. The combined organic layer was twice washed with a solution of50:50 water-brine, dried over sodium sulfate, and concentrated undervacuum. The residue was purified by silica gel chromatography. Elutionwith ethyl acetate-heptane (80:20 v/v) afforded the title compound (1.03g, 72%) as a colorless oil; TLC R_(f) 0.4 (solvent system 80:20 v/vethyl acetate-heptane); MS (ESI⁺) m/z 257.1 (M+H)⁺; ¹H NMR (CD₃OD) δ7.37-7.22 (m, 5H), 4.01 (q, J=6.71 Hz, 1H), 3.74-3.69 (m, 6H), 3.27-3.2(m, 1H), 3.09-2.97 (m, 1H), 1.37-1.34 (m, 3H); [α]^(T) _(λ)=α/cl,[α]^(21.9) _(D)=0.946/(0.01859 g/1.5 mL)(0.5)=+152.6° (c=1.24, CHCl₃).

(S)-(+)-dimethyl (3-methyl-2-oxo-4-phenylbutyl)phosphonate (15kb(i))

(S)-(+)-Dimethyl (3-methyl-2-oxo-4-phenylbutyl)phosphonate was preparedin the same manner as the second alternative preparation of(S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i))using the same sequence of reactions except that benzyl bromide was usedinstead of (3-bromopropyl)benzene. The crude product was purified bysilica gel chromatography. Elution with ethyl acetate-heptane (80:20v/v) afforded the title compound (680 mg) as a colorless oil; TLC R_(f)0.35 (solvent system: 80:20 v/v ethyl acetate:heptanes; MS (ESI⁺) m/z271.1 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.29-7.14 (m, 5H), 3.71 (dd, 6H, J=10.99,19.04 Hz), 3.12-2.89 (m, 4H), 2.58 (dd, 1H, J=7.69, 13.55 Hz), 1.11 (d,3H, J=6.96 Hz); [α]^(T) _(λ)=α/cl, [α]^(21.9) _(D)=0.249/(0.01501 g/1.5mL)(0.5)=+49.8° (c=1, CHCl₃).

Preparation of (S)-(+)-dimethyl(3-methyl-2-oxo-5-phenylpentyl)phosphonate (15lb(i))

(S)-Dimethyl (3-methyl-2-oxo-5-phenylpentyl)phosphonate was prepared inthe same manner as the second alternative preparation of(S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i))using the same sequence of reactions except that (2-bromoethyl)benzenewas used instead of (3-bromopropyl)benzene. The crude product waspurified by silica gel chromatography. Elution with ethylacetate-heptane (50:50 v/v) afforded the title compound (460 mg) as acolorless oil; TLC R_(f) 0.14 (solvent system: 50:50 v/v ethylacetate:heptanes); MS (ESI⁺) m/z 285.1 (M+H)⁺; ¹H-NMR (CDCl₃) δ7.30-7.24 (m, 2H), 7.21-7.14 (m, 3H), 3.76 (d, J=14.65 Hz, 3H), 3.76 (d,J=8.06 Hz, 3H), 3.16-3.03 (m, 2H), 2.77 (q, J=6.84 Hz, 1H), 2.64-2.56(m, 2H), 2.03 (ddt, 1H), 1.16 (d, J=6.96 Hz, 3H); [α]^(T) _(λ)=α/cl,[α]^(21.9) _(D)=0.052/(0.01998 g/1.5 mL)(0.5)=+7.81° (c=1.33, CHCl₃).

Preparation of (S)-(+)-dimethyl(3-methyl-2-oxo-7-phenylheptyl)phosphonate (15nb(i))

(S)-Dimethyl (3-methyl-2-oxo-7-phenylheptyl)phosphonate was prepared inthe same manner as the second alternative preparation of(S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i))using the same sequence of reactions except that (4-bromobutyl)benzenewas used instead of (3-bromopropyl)benzene. The crude product waspurified by silica gel chromatography. Elution with ethylacetate-heptane (50:50 v/v) afforded the title compound (2.84 g) as acolorless oil; TLC R_(f) 0.54 (solvent system: 100 v ethyl acetate); MS(ESI⁺) m/z 313.1 (M+H)⁺; ¹H-NMR (CDCl₃) δ 7.22-7.17 (m, 2H), 7.12-7.07(m, 3H), 3.82-3.68 (m, 6H), 3.07 (s, 1H), 3.01 (s, 1H), 2.71-2.62 (m,1H), 2.53 (t, J=7.69 Hz, 2H), 1.66-1.47 (m, 4H), 1.28-1.22 (m, 2H), 1.02(d, J=6.96 Hz, 3H); [α]^(T) _(λ)=α/cl, [α]^(21.9) _(D)=0.052/(0.01998g/1.5 mL)(0.5)=+7.81° (c=1.017, CHCl₃).

Preparation of (S)-(+)-dimethyl(3-methyl-2-oxo-8-phenyloctyl)phosphonate (15ob(i))

(S)-Dimethyl (3-methyl-2-oxo-8-phenyloctyl)phosphonate was prepared inthe same manner as the second alternative preparation of(S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i))using the same sequence of reactions except that (5-bromopentyl)benzenewas used instead of (3-bromopropyl)benzene. The crude product waspurified by silica gel chromatography. Elution with ethylacetate-heptane (50:50 v/v) afforded the title compound (1.06 g) as acolorless oil; TLC R_(f) 0.22 (solvent system: 50:50 v/v ethylacetate:heptanes); MS (ESI⁺) m/z 327.1 (M+H)⁺; ¹H-NMR (CDCl₃) δ7.27-7.24 (m, 2H), 7.19-7.14 (m, 3H), 3.79-3.76 (m, 6H), 3.13 (s, 1H),3.08 (s, 1H), 2.76-2.68 (m, 1H), 2.61-2.56 (m, 2H), 1.68-1.56 (m, 4H),1.35-1.28 (m, 4H), 1.09 (d, J=6.96 Hz, 3H); [α]^(T) _(λ)=α/cl,[α]^(21.9) _(D)=0.074/(0.01534 g/1.5 mL)(0.5)=+14.10° (c=1.02, CHCl₃).

Aspects of the present invention may be prepared utilizing aHorner-Emmons-Wadsworth-type procedure, according to the routesdescribed below in Schemes 9 and 10. The coupling of an aldehydeintermediate, such as those for which their preparations are describedand illustrated above (13a-f), with an organic phosphonate, such asthose that are commercially available or for which their preparationsare described and illustrated above (15), by way ofHorner-Emmons-Wadsworth olefination reaction, (Scheme 9, Step A)provides an α,β-unsaturated ketone compound intermediate (22a-f). TheC15-oxo group may be chemo- and stereoselectively reduced to thecorresponding C15-hydroxyl group as stereoisomeric alcohol mixtures (twoor more diastereomers, not necessarily of equal quantity) 23a-f (Scheme9, Step B), which may be subsequently separated by HPLC (Step C) toprovide a pure, single C15α-hydroxy diastereomer (24a-f) and a pure,single C15β-hydroxy (25a-f) diastereomers. The ester intermediatesresulting from these transformations may be subsequently subjected todeesterification conditions, such as base-catalyzed hydrolysis.Base-catalyzed hydrolysis of the esters provides the correspondingcarboxylic acid embodiments (26a-f and 27a-f). Organic β-ketophosphonates bearing a single chiral center, such as any of15(a-o)b(i-viii) and 15(a-o)c(i-viii), when coupled with aldehydes like13a-f in Scheme 9, Step A, followed by the stereoselective reduction(Step B), affords a set of four diastereomers which can be separatedusing HPLC to isolate each of its components (28a-f through 31a-f),C15α-C16β, C15α-C16α, C15β-C16β, and C15β-C16α as illustrated in Scheme10. The carboxylic acids (32a-f through 35a-f) of each of these fourdiastereomers may be obtained by base-catalyzed hydrolysis of thecorresponding esters using excess lithium hydroxide, potassium hydroxideor sodium hydroxide. Detailed procedures for preparing the sets ofdiastereomers are described below.

Aspects of the present invention may include compounds of formula (I)wherein R¹ is a carboxylic acid or carboxylic acid derivative,including, but not limited to, esters, amides, andN-(alkylsulfonyl)amides. Carboxylic acid derivatives may be preparedfrom the corresponding carboxylic acids by methods known in the art.General methods utilized for carrying out these transformations areillustrated in Scheme 11.

Compounds of formula (I), wherein R¹ is an amide orN-(alkylsulfonyl)amide, may be prepared from the corresponding compoundof formula (I), wherein R¹ is a carboxylic acid, by methods known in theart. Methods and strategies for amide bond formation have been reviewedby Montalbetti, G. N. and Falque, V. in Tetrahedron, 2005, 61,10827-10852. Amides and N-(alkylsulfonyl)amides may be prepared from thecorresponding carboxylic acids by proceeding through a carboxylactivation and subsequent amide bond formation by methods known in theart. Such procedures may comprise forming a mixture comprising thecarboxylic acid (limiting reagent), about one molar equivalent of anamine coupling partner, HNR¹⁰R¹¹, about one molar equivalent to about a50% molar excess of a coupling, condensing, or activating agent such as,but not limited to, N,N-dicyclohexylcarbodiimide (DCC),N,N-diisopropylcarbodiimide (DIC), carbonyl diimidazole (CDI), or1-ethyl-3-(3′-dimethylamino)carbodiimide hydrochloride (EDC or EDAC),benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP),benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU), orO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), and a solvent, such as, but not limited to, DMF, NMP,dichloromethane, THF, 1,4-dioxane, acetonitrile, or DME. The mixture mayfurther comprise about one to two molar equivalents of an amine basesuch as diisopropylethylamine (DIEA), triethylamine (TEA), or pyridine.The mixtures comprising an amine base may further comprise a catalyticamount of an additive such as DMAP. The mixtures comprising DCC, DIC, orEDC may further comprise about one molar equivalent of HOBt. Themixtures may be stirred at room temperature or may be warmed to promotethe coupling reaction for the time necessary to effect completion of thedesired coupling reaction. Reactions may be worked up and the amide orN-(alkylsulfonyl)amide product purified and isolated by methods known inthe art.

Compounds of formula (I), wherein R¹ is an ester, may be prepared fromthe corresponding compound of formula (I), wherein R¹ is a carboxylicacid, by methods known in the art. A variety of methods that may be usedis described by Larock, R. C. in Comprehensive Organic Transformations,VCH Publishers, Inc., New York, 1989, pp. 966-972, and referencestherein.

Aspects of the present invention may include compounds of formula (I)wherein R¹ is tetrazol-5-yl. Compounds of formula (I), wherein R¹ istetrazol-5-yl, may be prepared from the corresponding compound offormula (I), wherein R¹ is cyano, by using conditions and methods knownin the art, two of which are illustrated in Scheme 12.

Aspects of the present invention may include compounds of formula (I)wherein L⁴ is an ethylene group. These compounds may be obtained bysubjecting compounds of formula (I), wherein L⁴ is ethenylene orethynylene, to catalytic hydrogenation conditions, such as those knownin the art. Catalytic hydrogenation methods have been reviewed byRylander, P. N. in Hydrogenation Methods, Academic Press: New York,1985, Chapters 2-3.

Aspects of the present invention may further include compounds offormula (I), wherein L⁴ is —CH₂—CH₂— (ethylene), and L¹ comprises atleast one moiety or functional group, such as an alkenyl, alkynyl, orhalogen group, that may reduce under typical catalytic hydrogenationconditions. Preparation of these compounds may comprise a syntheticroute wherein the lower chain is first installed onto the difluorolactamring scaffold by, for example, an olefination or alkynylation reaction,as described herein, and the resulting 8+lower chain intermediate,wherein L⁴ is ethenylene or ethynylene, is subsequently reduced bycatalytic hydrogenation to provide the corresponding 8+lower chainintermediate wherein L⁴ is ethylene. Subsequent installation and, ifnecessary, chemical modification, of the upper chain would provide thecorresponding compound of formula (I) wherein L⁴ is ethylene.

The following Examples were prepared based on the reaction Schemes 9,Steps A -D and Scheme 10, Steps C and D.

Examples 1A-1I Step A: Preparation of methyl7-((5R)-3,3-difluoro-5-((E)-4-methyl-3-oxooct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate

To an ice cooled mixture consisting of dimethyl(3-methyl-2-oxohept-5-yn-1-yl)phosphonate (76 mg, 0.33 mmol) and(R)-methyl 7-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl) heptanoate(13a, 80 mg, 0.28 mmol) in THF (3 mL) was added lithium chloride (35 mg,0.83 mmol) followed by triethylamine (55 μL, 0.42 mmol) and the reactionstirred overnight, warming to room temperature. The reaction wasquenched with the addition of a saturated solution of aqueous ammoniumchloride and extracted with ethyl acetate. The combined organic phasewas dried over sodium sulfate and concentrated to a golden oil. Theresidue was purified by silica gel chromatography. Elution withmethanol:dichloromethane (1:300 v/v) to afford the title compound (76.6mg) as a clear oil; TLC R_(f) 0.80 (solvent system: 5:95 v/vmethanol-dichloromethane); ¹H-NMR (CDCl₃) δ 6.7-6.5 (m, 1H), 6.4 (d,1H), 4.3-4.2 (m, 2H), 3.0-2.8 (m, 1H), 2.8-2.6 (m, 1H) 2.5-2.2 (m, 6H),1.8 (s, 3H), 1.7-1.4 (m, 4H), 1.4-1.2 (m, 4H), 1.2 (d, 3H); MS (ESI⁺)m/z 398.1 (M+1), 420.1 (M+Na), (ESI⁻) m/z 396.1 (M−1).

Step B: Preparation of four-diastereomer mixture methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate

To a −40° C. solution consisting of methyl7-((5R)-3,3-difluoro-5-((E)-4-methyl-3-oxooct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(76 mg, 0.20 mmol) in methanol (5 mL) was added cerium chlorideheptahydrate (75 mg, 0.20 mmol) in one portion. The reaction mixture wasstirred for 15 minutes, and cooled to −78° C. for 20 minutes. Sodiumborohydride (15 mg, 0.40 mmol) was added and the reaction was stirredfor 3 hours, quenched with equal parts water and saturated ammoniumchloride and warmed to room temperature. The reaction mixture wasextracted with ethyl acetate. The combined organic phase was dried oversodium sulfate and concentrated to a cloudy white oil. The residue waspurified by silica gel chromatography. Elution withmethanol-dichloromethane (1:200 v:v) to afford the title compound (70mg) as a clear oil. R_(f) 0.50 (solvent system: 5:95 v/vmethanol:dichloromethane).

Step C: Preparation of methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 1A), methyl7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 1B), methyl7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 1D) and methyl7-((R)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 1E)

From the stereoisomeric mixture comprising the four-diastereomer mixturemethyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(70 mg, prepared in Step B of this Example above) were separated thesingle isomers methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 1A) and methyl7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 1B), and the diastereomeric mixture (at C16) methyl7-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 1C) by prep HPLC. The separations were performed on an AgilentSemi-Prep instrument equipped with an ultraviolet detector at 205 nm andusing ultraviolet detector at 205 nm; Luna Silica 5μ 250×10 mm columneluting with a mobile phase of heptanes-ethanol (96:4 v/v).

Example 1A (7.6 mg); a clear oil; prep HPLC retention time 24.1-25.0minutes; ¹H-NMR (CDCl₃) δ 6.9-6.8 (m, 1H), 6.6-6.5 (m, 1H), 4.2-4.1 (m,1H), 3.7 (s, 1H), 3.6-3.5 (m, 1H) 3.1-2.9 (m, 1H), 2.8-2.6 (br, 1H)2.4-2.0 (m, 7H), 1.8 (s, 3H), 1.7-1.4 (m, 4H), 1.4-1.2 (m, 4H), 1.0-0.9(d, 3H); MS (ESI⁺) m/z 400.2 (M+1), 422.1 (M+Na).

Example 1B (5.8 mg); a clear oil; prep HPLC retention time 22.5-23.6minutes; ¹H-NMR (CDCl₃) δ 6.9-6.8 (m, 1H), 6.6-6.5 (m, 1H), 4.2-4.1 (m,1H), 3.7 (s, 1H), 3.6-3.5 (m, 1H) 3.1-2.9 (m, 1H), 2.8-2.6 (br, 1H)2.4-2.0 (m, 7H), 1.8 (s, 3H), 1.7-1.4 (m, 4H), 1.4-1.2 (m, 4H), 1.0-0.9(d, 3H); MS (ESI⁺) m/z 400.2 (M+1), 422.1 (M+Na).

The diastereomeric mixture methyl7-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example IC) was separated to afford the pure diastereomers methyl7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 1D), and methyl7-((R)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 1E), by prep HPLC.

Agilent Semi-Prep instrument; ultraviolet detector at 205 nm; LunaSilica 5μ 250×10 mm column; mobile phase of heptanes-ethanol (98:2 v/v).

Example 1D (15.5 mg); a clear oil; HPLC retention time 48.4-55.7 min;¹H-NMR (CDCl₃) δ 6.9-6.8 (m, 1H), 6.6-6.5 (m, 1H), 4.2-4.1 (m, 1H), 3.7(s, 1H), 3.6-3.5 (m, 1H) 3.1-2.9 (m, 1H), 2.8-2.6 (br, 1H) 2.4-2.0 (m,7H), 1.8 (s, 3H), 1.7-1.4 (m, 4H), 1.4-1.2 (m, 4H), 1.0-0.9 (d, 3H); MS(ESI+) m/z 400.2 (M+1), 422.1 (M+Na).

Example 1E (4.3 mg); a clear oil; HPLC retention time 42.7-47.3 min;¹H-NMR (CDCl₃) δ 6.9-6.8 (m, 1H), 6.6-6.5 (m, 1H), 4.2-4.1 (m, 1H), 3.7(s, 1H), 3.6-3.5 (m, 1H) 3.1-2.9 (m, 1H), 2.8-2.6 (br, 1H) 2.4-2.0 (m,7H), 1.8 (s, 3H), 1.7-1.4 (m, 4H), 1.4-1.2 (m, 4H), 1.0-0.9 (d, 3H); MS(ESI+) m/z 400.2 (M+1), 422.1 (M+Na).

Step D1: Preparation of7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 1F)

To a solution of methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 1A, 5.6 mg, 0.014 mmol) in methanol (0.15 mL) was added lithiumhydroxide (1M in H₂O, 0.06 mL, 0.06 mmol) and the reaction mixture wasstirred overnight. The reaction was quenched with the addition of KHSO₄and brine and the organic material was extracted with ethyl acetate. Theorganic phase was concentrated, redissolved in ethyl acetate, filtered,and concentrated to give 5.7 mg of a clear oil; TLC R_(f) 0.45 (solventsystem: 90:10:1 v/v dichloromethane-methanol-acetic acid); ¹H-NMR(CDCl₃) δ 6.9-6.8 (m, 1H), 6.6-6.5 (m, 1H), 4.4-4.3 (m, 1H), 4.2-4.1 (m,1H), 3.6-3.5 (m, 1H) 3.1-2.9 (m, 1H), 2.8-2.6 (br, 1H) 2.4-2.0 (m, 7H),1.9-1.7 (s, 3H), 1.7-1.4 (m, 4H), 1.4-1.1 (m, 4H), 1.0-0.9 (d, 3H); MS(ESI⁺) m/z 368.1 (M+1), 408.1 (M+Na).

Step D2: Preparation of7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 1G)

Hydrolysis of methyl7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate,done in the same manner as Step D1 above, afforded 5.4 mg of a clearoil; TLC R_(f) 0.45 (solvent system: 90:10:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 6.9-6.8 (m, 1H),6.6-6.5 (m, 1H), 4.4-4.3 (m, 1H), 4.2-4.1 (m, 1H), 3.6-3.5 (m, 1H)3.1-2.9 (m, 1H), 2.8-2.6 (br, 1H) 2.4-2.0 (m, 7H), 1.9-1.7 (s, 3H),1.7-1.4 (m, 4H), 1.4-1.1 (m, 4H), 1.0-0.9 (d, 3H); MS (ESI⁺) m/z 368.1(M+1), 408.1 (M+Na).

Step D3: Preparation of7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 1H)

Step D4: Preparation of7-((R)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 1I)

The hydrolysis of each of the following carboxylic ester Examples wereperformed in the same manner as described in Example 1, Step D1, usingaqueous lithium hydroxide (though in some cases sodium hydroxide orpotassium hydroxide can and was used instead of lithium hydroxide) toafford the analogous carboxylic acid Examples.

Examples 2A-2D Step A, B and C, Preparation of methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 2A) and methyl7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 2B)

Methyl7-((5R)-3,3-difluoro-5-((4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(61 mg) was prepared by the method described in Example 1, Steps A andB, except that (S)-(+)-dimethyl (3-methyl-2-oxooct-5-yn-1-yl)phosphonate(15bc(i)) was used instead of (±)-dimethyl(3-methyl-2-oxohept-5-yn-1-yl)phosphonate (15ab(i)/15ac(i)) in Step A.

Step C: The pure diastereomers of Example 2A and Example 2B wereisolated following separation by prep HPLC.

Agilent Semi-Prep instrument; ultraviolet detector at 233 nm; ChiralpakIA 250×4.6 mm column; mobile phase of heptane-ethanol (98:2 v/v).

Example 2A (8.1 mg); a clear oil; HPLC retention time 57 min; MS (ESI⁺)m/z 414.1 (M+1) (ESI⁻) m/z 412.1 (M−1).

Example 2B (20.5 mg); a clear oil; HPLC retention time 42 min; MS (ESI⁺)m/z 414.1 (M+1) (ESI⁻) m/z 412.1(M−1).

Step B: Alternative preparation of methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 2A) and methyl7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 2B)

To a solution consisting of methyl7-((R)-3,3-difluoro-5-((S,E)-4-methyl-3-oxonon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(169 mg, 0.460 mmol) and (R)-Corey-Bakshi-Shibata catalyst (1 M in THF,0.46 mmol) in dichloromethane (100 mL) at −40° C. was added catecholborane (1 M in THF, 0.46 mmol) dropwise over 10 minutes. The reactionmixture was stirred overnight, warming to room temperature, thenquenched with 1 N HCl (10 mL). The reaction mixture was extracted withethyl acetate. The combined organic phase was dried over sodium sulfateand concentrated to a cloudy brown oil. The residue was purified bysilica gel chromatography. Elution with methanol:dichloromethane (1:200v:v) afforded a mixture of 2A and 2B (52 mg) as a clear oil; R_(f) 0.65(solvent system: 7:93 v/v methanol:dichloromethane).

The diastereomers were separated and purified diastereomer 2A (15.2 mg)was isolated using the prep HPLC method described in Step C of theoriginal preparation of this compound above.

Step D1: Preparation of7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 2C)

5.9 mg of a clear oil; TLC R_(f) 0.45 (solvent system: 95:5:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 5.9-5.8 (m, 1H),5.6-5.5 (m, 1H), 4.2-4.1 (m, 2H), 3.7-3.5 (m, 1H), 3.1-2.9 (m, 1H),2.8-2.7 (br s, 1H), 2.4-2.3 (t, 2H). 2.3-2.1 (m, 5H), 1.9-1.8 (m, 1H),1.7-1.5 (m, 5H), 1.4-1.2 (m, 4H), 1.1 (t, 3H), 1.0 (d, 3H); ¹⁹F-NMR(CDCl₃) δ −103.5 (d, 1F), −105.5 (d, 1F); MS (ESI⁺) m/z 400 (M+1), MS(ESI⁻) m/z 398 (M−1).

Step D2: Preparation of7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 2D)

14.8 mg of a clear oil; TLC R_(f) 0.45 (solvent system: 95:5:1 v/vdichloromethane-methanol-acetic acid); MS (ESI⁺) m/z 400 (M+1), MS(ESI⁻) m/z 398 (M−1).

Methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate

Example 4 Methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate

Example 5 Methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate

Examples 6A-6F Steps A, B, and C: Preparation of methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 6A), methyl7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 6B), and methyl7-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 6C)

Methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoatewas prepared by the method described in Example 1, Steps A and B, exceptthat (±)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate(15mb(i)/15mc(i)) was used instead of (±)-dimethyl(3-methyl-2-oxohept-5-yn-1-yl)phosphonate (15ab(i)/15ac(i)) in Step A.

Step C: From the stereoisomeric mixture comprising the four-diastereomermixture methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoatewere separated the single isomers methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 6A) and methyl7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 6B), and the diastereomeric mixture (at C16) methyl7-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 6C) by prep HPLC. The separations were performed on an AgilentSemi-Prep instrument equipped with an ultraviolet detector at 205 nm andusing ultraviolet detector at 205 nm; Luna Silica 5μ 250×10 mm columneluting with a mobile phase of heptanes-ethanol (96:4 v/v).

Example 6A (3.3 mg); a clear oil; prep HPLC retention time 20.9-21.8minutes; ¹H-NMR (CDCl₃) δ 7.3 (t, 2H), 7.2 (d, 3H), 5.9-5.7 (m, 1H),5.5-5.4 (m, 1H), 4.2-4.0 (m, 1H), 3.7 (s, 3H), 3.6-3.5 (m, 1H), 3.0-2.9(m, 1H), 2.8-2.6 (br, 1H), 2.6 (t, 2H), 2.4-2.0 (m, 6H), 1.8-1.4 (m,7H), 1.4-1.0 (m, 6H), 0.9 (d, 3H); MS (ESI⁺) m/z 466.4 (M+1), 488.5(M+Na).

Example 6B (10.1 mg); a clear oil; prep HPLC retention time 19.6-20.7minutes; ¹H-NMR (CDCl₃) δ 7.3 (t, 2H), 7.2 (d, 3H), 5.9-5.7 (m, 1H),5.5-5.4 (m, 1H), 4.2-4.0 (m, 1H), 3.7 (s, 3H), 3.6-3.5 (m, 1H), 3.0-2.9(m, 1H), 2.8-2.6 (br, 1H), 2.6 (t, 2H), 2.4-2.0 (m, 6H), 1.8-1.4 (m,7H), 1.4-1.0 (m, 6H), 0.9 (d, 3H); MS (ESI+) m/z 466.4 (M+1), 488.5(M+Na).

Example 6C (57.7 mg); a clear oil; prep HPLC retention time 16.2-18.6minutes; ¹H-NMR (CDCl₃) δ 7.3 (t, 2H), 7.2 (d, 3H), 5.9-5.7 (m, 1H),5.5-5.4 (m, 1H), 4.2-4.0 (m, 1H), 3.7 (s, 3H), 3.6-3.5 (m, 1H), 3.0-2.9(m, 1H), 2.8-2.6 (br, 1H), 2.6 (t, 2H), 2.4-2.0 (m, 6H), 1.8-1.4 (m,7H), 1.4-1.0 (m, 6H), 0.9 (d, 3H); MS (ESI⁺) m/z 466.4 (M+1), 488.5(M+Na).

Step D1: Preparation of7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 6D)

3.0 mg of a clear oil; TLC R_(f) 0.45 (solvent system: 90:10:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 7.3 (t, 2H), 7.2(d, 3H), 5.9-5.7 (m, 1H), 5.5-5.4 (m, 1H), 4.2-4.0 (m, 2H), 3.6-3.5 (m,1H), 3.0-2.9 (m, 1H), 2.8-2.6 (br, 1H), 2.6 (t, 2H), 2.4-2.0 (m, 6H),1.8-1.4 (m, 7H), 1.4-1.0 (m, 6H), 0.9 (dt, 3H); MS (ESI⁺) m/z 466.2(M+1), 488.2 (M+Na).

Step D2: Preparation of7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 6E)

7.7 mg of a clear oil; TLC R_(f) 0.45 (solvent system: 90:10:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 7.3 (t, 2H), 7.2(d, 3H), 5.9-5.7 (m, 1H), 5.5-5.4 (m, 1H), 4.2-4.0 (m, 2H), 3.6-3.5 (m,1H), 3.0-2.9 (m, 1H), 2.8-2.6 (br, 1H), 2.6 (t, 2H), 2.4-2.0 (m, 6H),1.8-1.4 (m, 7H), 1.4-1.0 (m, 6H), 0.9 (dt, 3H); MS (ESI⁺) m/z 466.2(M+1), 488.2 (M+Na).

Step D3: Preparation of7-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 6F)

8.9 mg of a clear oil; TLC R_(f) 0.45 (solvent system: 90:10:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 7.3 (t, 2H), 7.2(d, 3H), 5.9-5.7 (m, 1H), 5.5-5.4 (m, 1H), 4.2-4.0 (m, 2H), 3.6-3.5 (m,1H), 3.0-2.9 (m, 1H), 2.8-2.6 (br, 1H), 2.6 (t, 2H), 2.4-2.0 (m, 6H),1.8-1.4 (m, 7H), 1.4-1.0 (m, 6H), 0.9 (dt, 3H); MS (ESI⁺) m/z 466.2(M+1), 488.2 (M+Na).

Example 7 Methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate

Example 8 Methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate

Examples 9A-9D Steps A, B, and C: Preparation of methyl7-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 9A) and methyl7-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 9B)

Methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoatewas prepared by the method described in Examples 1, Steps A and B,except that dimethyl (2-oxoheptyl)phosphonate (15ga) was used instead of(±)-dimethyl (3-methyl-2-oxohept-5-yn-1-yl)phosphonate (15ab(i)/15ac(i))in Step A.

Step C: From the diastereomeric mixture methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoatewere separated the single isomers methyl7-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 9A) and methyl7-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 9B) by prep HPLC. The separations were performed on an AgilentSemi-Prep instrument equipped with an ultraviolet detector at 205 nm andusing ultraviolet detector at 205 nm; Luna Silica 5μ 250×10 mm columneluting with a mobile phase of heptanes-ethanol (93:7 v/v).

Example 9A (21.6 mg); a clear oil; prep HPLC retention time 12.1-12.9minutes; ¹H-NMR (CDCl₃) δ 6.9-6.8 (m, 1H), 6.6-6.4 (m, 1H), 4.3-4.1 (m,2H), 3.7 (s, 3H), 3.6-3.5 (m, 1H), 3.1-2.9 (m, 1H), 2.8-2.6 (m, 1H),2.4-2.1 (m, 4H), 2.0-1.7 (br, 1H) 1.7-1.4 (m, 6H), 1.4-1.2 (m, 10H), 0.9(t, 3H); MS (ESI⁺) m/z 390.2 (M+1).

Example 9B (46.5 mg); a clear oil; prep HPLC retention time 10.6-11.5minutes; ¹H-NMR (CDCl3) δ 6.9-6.8 (m, 1H), 6.6-6.4 (m, 1H), 4.3-4.1 (m,2H), 3.7 (s, 3H), 3.6-3.5 (m, 1H), 3.1-2.9 (m, 1H), 2.8-2.6 (m, 1H),2.4-2.1 (m, 4H), 2.0-1.7 (br, 1H) 1.7-1.4 (m, 6H), 1.4-1.2 (m, 10H), 0.9(t, 3H); MS (ESI⁺) m/z 390.2 (M+1).

Step D1: Preparation of7-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 9C)

14.5 mg of a clear oil; TLC R_(f) 0.40 (solvent system: 90:10:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 6.9-6.8 (m, 1H),6.5-6.4 (m, 1H), 4.2-4.0 (m, 2H), 3.6-3.5 (m, 1H), 3.1-3.0 (m, 1H),2.8-2.6 (m, 1H), 2.4-2.0 (m, 4H), 1.7-1.5 (m, 6H), 1.5-1.0 (m, 10H), 0.9(t, 3H); MS (ESI⁺) m/z 376.2 (M+1), 398.1 (M+Na).

Step D2: Preparation of7-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 9D)

14.0 mg of a clear oil; TLC R_(f) 0.40 (solvent system: 90:10:1 v/vdichloromethane-methanol-acetic acid);); ¹HNMR (CDCl₃) δ 6.9-6.8 (m,1H), 6.5-6.4 (m, 1H), 4.2-4.0 (m, 2H), 3.6-3.5 (m, 1H), 3.1-3.0 (m, 1H),2.8-2.6 (m, 1H), 2.4-2.0 (m, 4H), 1.7-1.5 (m, 6H), 1.5-1.0 (m, 10H), 0.9(t, 3H); MS (ESI⁺) m/z 376.2 (M+1), 398.1 (M+Na).

Examples 10A-10D Steps A, B, and C: Preparation of methyl7-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 10A) and methyl7-((R)-3,3-difluoro-5-((R,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 10B)

Methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoatewas prepared by the method described in Examples 1, Steps A and B,except that dimethyl (2-oxo-6-phenylhexyl)phosphonate (15ma) was usedinstead of (±)-dimethyl (3-methyl-2-oxohept-5-yn-1-yl)phosphonate(15ab(i)/15ac(i)) in Step A.

Step C: From the diastereomeric mixture methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoatewere separated the single isomers methyl7-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 10A) and methyl7-((R)-3,3-difluoro-5-((R,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate(Example 10B) by prep HPLC. The separations were performed on an AgilentSemi-Prep instrument equipped with an ultraviolet detector at 205 nm andusing ultraviolet detector at 205 nm; Luna Silica 5μ 250×10 mm columneluting with a mobile phase of heptanes-ethanol (93:7 v/v).

Example 10A (14.4 mg); a clear oil; prep HPLC retention time 15.8-17.0minutes; ¹H-NMR (CDCl₃) δ 7.3-7.2 (m, 2H), 7.2-7.1 (m, 3H), 5.9-5.8 (m,1H), 5.5-5.4 (m, 1H), 4.2-4.1 (m, 1H), 4.1-4.0 (m, 1H), 3.65 (s, 3H),3.6-3.5 (m, 1H), 3.0-2.9 (m, 1H), 2.6 (t, 3H), 2.3 (t, 3H), 1.9-1.7 (br,1H), 1.7-1.5 (m, 8H) 1.4-1.2 (m, 6H); ¹⁹F-NMR (CDCl₃) δ −103.5 (d, 1F),−105.5 (d, 1F); MS (ESI⁺) m/z 452.2 (M+1) 474.2 (M+Na).

Example 10B (42.2 mg); a clear oil; prep HPLC retention time 13.7-15.1minutes; ¹H-NMR (CDCl₃) δ 7.3-7.2 (m, 2H), 7.2-7.1 (m, 3H), 5.9-5.8 (m,1H), 5.5-5.4 (m, 1H), 4.2-4.1 (m, 1H), 4.1-4.0 (m, 1H), 3.65 (s, 3H),3.6-3.5 (m, 1H), 3.0-2.9 (m, 1H), 2.6 (t, 3H), 2.3 (t, 3H), 1.9-1.7 (br,1H), 1.7-1.5 (m, 8H) 1.4-1.2 (m, 6H); ¹⁹F-NMR (CDCl₃) δ −103.5 (d, 1F),−105.5 (d, 1F); MS (ESI⁺) m/z 452.2 (M+1) 474.2 (M+Na).

Step D1: Preparation of7-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 10C)

16.5 mg of a clear oil; TLC R_(f) 0.35 (solvent system: 90:10:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 7.3-7.2 (m, 2H),7.2-7.1 (m, 3H), 5.9-5.8 (m, 1H), 5.5-5.4 (m, 1H), 4.2-4.1 (m, 1H),4.1-4.0 (m, 1H), 3.6-3.5 (m, 1H), 3.0-2.9 (m, 1H), 2.6 (t, 3H), 2.2 (t,3H), 2.2-2.1 (m, 1H), 1.7-1.5 (m, 8H), 1.5-1.1 (m, 6H); ¹⁹F-NMR (CDCl₃)δ −103.5 (d, 1F), −105.5 (d, 1F); MS (ESI⁻) m/z 436.2 (M−1).

Step D2: Preparation of7-((R)-3,3-difluoro-5-((R,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid (Example 10D)

30.3 mg of a clear oil; TLC R_(f) 0.35 (solvent system: 90:10:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 7.3-7.2 (m, 2H),7.2-7.1 (m, 3H), 5.9-5.8 (m, 1H), 5.5-5.4 (m, 1H), 4.2-4.1 (m, 1H),4.1-4.0 (m, 1H), 3.6-3.5 (m, 1H), 3.0-2.9 (m, 1H), 2.6 (t, 3H), 2.2 (t,3H), 2.2-2.1 (m, 1H), 1.7-1.5 (m, 8H), 1.5-1.1 (m, 6H); ¹⁹F-NMR (CDCl₃)δ −103.5 (d, 1F), −105.5 (d, 1F); MS (ESI⁻) m/z 436.2 (M−1).

Example 114-(2-((R)-3,3-Difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid

Examples 12A-12F Steps A, B, and C: Preparation of methyl4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate(Example 12A), methyl4-(2-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate(Example 12B), and methyl4-(2-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate(Example 12C)

Methyl4-(2-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoatewas prepared by the method described in Example 1, Steps A and B, exceptthat (R)-methyl4-(2-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)ethyl)benzoate (13b)was used instead of (R)-methyl7-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)heptanoate (13a) and(±)-dimethyl (3-methyl-2-oxooct-5-yn-1-yl)phosphonate (15bb(i)/15bc(i))was used instead of (±)-dimethyl(3-methyl-2-oxohept-5-yn-1-yl)phosphonate (15ab(i)/15ac(i)) in Step A.

Step C: From the stereoisomeric mixture comprising the four-diastereomermixture methyl4-(2-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoatewere separated the single isomers methyl4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate(Example 12A) and methyl4-(2-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate(Example 12B), and the diastereomeric mixture (at C16) methyl4-(2-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate(Example 12C) by prep HPLC.

Agilent Semi-Prep instrument; ultraviolet detector at 205 nm; LunaSilica 5μ 250 mm×10 mm column; mobile phase of heptane-ethanol (98:2v/v).

Example 12A (6.0 mg); a clear oil; HPLC retention time 78.9-83.9minutes; ¹H-NMR (CDCl₃) δ 8.0 (d, 2H), 7.3-7.2 (m, 2H), 5.7-5.6 (m, 1H),5.5-5.4 (m, 1H), 4.2-4.1 (m, 1H), 3.9 (s, 3H), 3.9-3.8 (m, 1H), 3.8-3.7(m, 1H), 3.3-3.2 (m, 1H), 3.1-3.0 (m, 1H), 3.0-2.9 (m, 1H), 2.7-2.5 (m,1H), 2.2-2.1 (m, 6H), 1.2-1.1 (t, 3H), 1.0-0.9 (d, 3H); MS (ESI⁺) m/z456.1 (M+Na).

Example 12B (7.0 mg); a clear oil; HPLC retention time 72.7-77.6minutes; ¹H-NMR (CDCl₃) δ 8.0 (d, 2H), 7.3-7.2 (m, 2H), 5.7-5.6 (m, 1H),5.5-5.4 (m, 1H), 4.3-4.2 (m, 1H), 3.9 (s, 3H), 3.9-3.8 (m, 1H), 3.8-3.7(m, 1H), 3.3-3.2 (m, 1H), 3.1-3.0 (m, 1H), 3.0-2.9 (m, 1H), 2.7-2.5 (m,1H), 2.2-2.1 (m, 6H), 1.2-1.1 (t, 3H), 1.0-0.9 (d, 3H); MS (ESI⁺) m/z456.1 (M+Na).

Example 12C (20.0 mg); a clear oil; HPLC retention time 59.6-68.8minutes; ¹H-NMR (CDCl₃) δ 8.0 (d, 2H), 7.3-7.2 (m, 2H), 5.7-5.6 (m, 1H),5.5-5.4 (m, 1H), 4.3-4.2 (m, 0.5H), 4.2-4.1 (m, 0.5H), 3.9 (s, 3H),3.9-3.8 (m, 1H), 3.8-3.7 (m, 1H), 3.3-3.2 (m, 1H), 3.1-3.0 (m, 1H),3.0-2.9 (m, 1H), 2.7-2.5 (m, 1H), 2.2-2.1 (m, 6H), 1.2-1.1 (t, 3H),1.0-0.9 (d, 3H); MS (ESI⁺) m/z 456.1 (M+Na).

Step D1: Preparation of4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid (Example 12D)

5.0 mg as a colorless oil; TLC R_(f) 0.30 (solvent system: 96:4:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 8.0 (d, 2H),7.4-7.3 (m, 2H), 5.9-5.8 (m, 1H), 5.5-5.4 (m, 1H), 4.2-4.0 (m, 2H),3.9-3.8 (m, 1H), 3.4-3.3 (m, 1H), 3.1-3.0 (m, 1H), 3.0-2.9 (m, 1H),2.8-2.7 (m, 1H), 2.3-2.2 (m, 2H), 2.2-2.1 (m, 2H), 2.1-2.0 (m, 1H),1.8-1.7 (m, 1H) 1.2-1.1 (t, 3H), 1.0-0.9 (d, 3H); MS (ESI⁺) m/z 442.1(M+Na), (ESI⁻) m/z 418.2.

Step D2: Preparation of4-(2-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid (Example 12E)

4.8 mg as a colorless oil; TLC R_(f) 0.30 (solvent system: 96:4:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 8.0 (d, 2H),7.4-7.3 (m, 2H), 5.9-5.8 (m, 1H), 5.5-5.4 (m, 1H), 4.2-4.0 (m, 2H),3.9-3.8 (m, 1H), 3.4-3.3 (m, 1H), 3.1-3.0 (m, 1H), 3.0-2.9 (m, 1H),2.8-2.7 (m, 1H), 2.3-2.2 (m, 2H), 2.2-2.1 (m, 2H), 2.1-2.0 (m, 1H),1.8-1.7 (m, 1H) 1.2-1.1 (t, 3H), 1.0-0.9 (d, 3H); MS (ESI⁺) m/z 442.1(M+Na), (ESI⁻) m/z 418.2.

Step D3: Preparation of4-(2-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid (Example 12F)

14.6 mg as a colorless oil; TLC R_(f) 0.30 (solvent system: 96:4:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 8.0 (2H, d),7.4-7.3 (2H, m), 5.9-5.8 (1H, m), 5.5-5.4 (1H, m), 4.2-4.0 (2H, m),3.9-3.8 (1H, m), 3.4-3.3 (1H, m), 3.1-3.0 (1H, m), 3.0-2.9 (1H, m),2.8-2.7 (1H, m), 2.3-2.2 (2H, m), 2.2-2.1 (2H, m), 2.1-2.0 (1H, m),1.8-1.7 (1H, m) 1.2-1.1 (3H, t), 1.0-0.9 (3H, d); MS (ESI⁺) m/z 442.1(M+Na), (ESI⁻) m/z 418.2.

Example 13D4-(2-((R)-3,3-Difluoro-5-((3S,4S,E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid

Example 14D4-(2-((R)-3,3-Difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid

Example 15D4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid

Example 16D4-(2-((R)-3,3-Difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid

Example 17C4-(2-((R)-3,3-Difluoro-5-((S,E)-3-hydroxyoct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid

Example 18C4-(2-((R)-3,3-Difluoro-5-((S,E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid

Example 19C4-(2-((R)-3,3-Difluoro-5-((S,E)-3-hydroxydec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid

Example 20C4-(2-((R)-3,3-Difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid

Examples 21A-21D Steps A, B, and C: Preparation of methyl4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate(Example 21A) and methyl4-(2-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate(Example 21B)

Methyl4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoatewas prepared by the method described in Example 9, Steps A and B, exceptthat (R)-methyl4-(2-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)ethyl)benzoate (13b)was used instead of (R)-methyl7-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl) heptanoate (13a) in StepA.

Step C: From the diastereomeric mixture methyl4-(2-((5R)-3,3-difluoro-5-((E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoatewere separated the single isomers methyl4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate(Example 21A) and methyl4-(2-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate(Example 21B) by prep HPLC. The separations were performed on an AgilentSemi-Prep instrument equipped with an ultraviolet detector at 205 nm andusing ultraviolet detector at 205 nm; Luna Silica 5μ 250×10 mm columneluting with a mobile phase of heptanes-ethanol (94:6 v/v).

Example 21A (12 mg); a clear oil; prep HPLC retention time 15.9-16.3minutes; ¹H-NMR (CDCl₃) δ 8.0 (d, 2H), 7.3-7.2 (m, 2H), 5.7-5.6 (m, 1H),5.4-5.3 (m, 1H), 4.2-4.1 (m, 1H), 3.9 (s, 3H), 3.9-3.8 (m, 1H), 3.8-3.7(m, 1H), 3.3-3.2 (m, 1H), 3.0-2.9 (m, 2H), 2.6-2.5 (m, 1H), 2.2-2.1 (m,1H), 1.6 (br, 1H), 1.6-1.5 (m, 2H), 1.4-1.3 (m, 6H), 0.95-0.85 (m, 3H);MS (ESI⁺) m/z 432.2 (M+Na).

Example 21B (24.0 mg); a clear oil; prep HPLC retention time 14.2-14.6minutes; ¹H-NMR (CDCl₃) δ 8.0 (d, 2H), 7.3-7.2 (m, 2H), 5.7-5.6 (m, 1H),5.4-5.3 (m, 1H), 4.2-4.1 (m, 1H), 3.9 (s, 3H), 3.9-3.8 (m, 1H), 3.8-3.7(m, 1H), 3.3-3.2 (m, 1H), 3.0-2.9 (m, 2H), 2.6-2.5 (m, 1H), 2.2-2.1 (m,1H), 1.6 (br, 1H), 1.6-1.5 (m, 2H), 1.4-1.3 (m, 6H), 0.95-0.85 (m, 3H);MS (ESI⁺) m/z 432.2 (M+Na).

Step D1: Preparation of4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid (Example 21C)

8.0 mg of a clear oil; TLC R_(f) 0.35 (solvent system: 96:4:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 8.0 (d, 2H), 7.8(d, 2H) 5.9-5.8 (m, 1H), 5.4-5.3 (m, 1H), 4.1-4.0 (m, 2H), 3.8-3.7 (m,1H), 3.4-3.3 (m, 1H), 3.0-2.9 (m, 2H), 2.8-2.7 (m, 1H), 2.3-2.2 (m, 1H),1.6-1.2 (m, 9H), 1.0-0.9 (m, 3H); MS (ESI⁻) m/z 394 (M−1).

Step D2: Preparation of4-(2-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid (Example 21D)

16.6 mg of a clear oil; TLC R_(f) 0.35 (solvent system: 96:4:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 8.0 (d, 2H), 7.8(d, 2H) 5.9-5.8 (m, 1H), 5.4-5.3 (m, 1H), 4.1-4.0 (m, 2H), 3.8-3.7 (m,1H), 3.4-3.3 (m, 1H), 3.0-2.9 (m, 2H), 2.8-2.7 (m, 1H), 2.3-2.2 (m, 1H),1.6-1.2 (m, 9H), 1.0-0.9 (m, 3H); MS (ESI⁻) m/z 394 (M−1).

Example 22C4-(2-((R)-3,3-Difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid

Example 23D5-(3-((R)-3,3-Difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid

Example 24A-24F Step A, B, and C: Preparation of methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 24A), methyl5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 24B), and methyl5-(3-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 24C)

Methyl5-(3-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewas prepared by the method described in Examples 12, Steps A and B,except that (R)-methyl5-(3-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(130) was used instead of (R)-methyl4-(2-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)ethyl)benzoate (13b) inStep A.

Step C: From the stereoisomeric mixture comprising the four-diastereomermixture methyl5-(3-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewere separated the single isomers methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 24A) and methyl5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 24B), and the diastereomeric mixture (at C16) methyl5-(3-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 24C) by prep HPLC.

Agilent Semi-Prep instrument; ultraviolet detector at 205 nm; LunaSilica 5μ 250 mm×10 mm column; mobile phase of heptane-ethanol (98:2v/v).

Example 24A (4.0 mg); a clear oil; HPLC retention time 78.9-83.9minutes; ¹H-NMR (CDCl₃) δ 7.6 (d, 1H), 6.8 (d, 1H), 5.9-5.8 (m, 1H),5.6-5.5 (m, 1H), 4.2-4.1 (m, 2H), 3.85 (s, 3H), 3.7-3.6 (m, 1H), 3.1-3.0(m, 1H), 2.9-2.8 (t, 2H), 2.7-2.6 (m, 1H), 2.3-2.1 (m, 6H), 2.0-1.9 (m,2H), 1.8-1.7 (m, 1H), 1.2-1.1 (t, 3H), 1.0-0.9 (d, 3H); ¹⁹F-NMR (CDCl₃)δ −103.5 (d, 1F), −105.5 (d, 1F); MS (ESI⁺) m/z 471.1 (M+Na).

Example 24B (5.0 mg); a clear oil; HPLC retention time 72.7-77.6minutes; ¹H-NMR (CDCl₃) δ 7.6 (d, 1H), 6.8 (d, 1H), 5.9-5.8 (m, 1H),5.6-5.5 (m, 1H), 4.4-4.2 (m, 1H), 4.2-4.1 (m, 1H), 3.85 (s, 3H), 3.7-3.6(m, 1H), 3.1-3.0 (m, 1H), 2.9-2.8 (t, 2H), 2.7-2.6 (m, 1H), 2.3-2.1 (m,6H), 2.0-1.9 (m, 2H), 1.8-1.7 (m, 1H), 1.2-1.1 (t, 3H), 1.0-0.9 (d, 3H);¹⁹F-NMR (CDCl₃) δ −103.5 (d, 1F), −105.5 (d, 1F); MS (ESI⁺) m/z 471.1(M+Na).

Example 24C (16.4 mg); a clear oil; HPLC retention time 59.6-68.8minutes; ¹H-NMR (CDCl₃) δ 7.6 (d, 1H), 6.8 (d, 1H), 5.9-5.8 (m, 1H),5.6-5.5 (m, 1H), 4.4-4.2 (m, 0.5H), 4.2-4.1 (m, 1.5H), 3.85 (s, 3H),3.7-3.6 (m, 1H), 3.1-3.0 (m, 1H), 2.9-2.8 (t, 2H), 2.7-2.6 (m, 1H),2.3-2.1 (m, 6H), 2.0-1.9 (m, 2H), 1.8-1.7 (m, 1H), 1.2-1.1 (t, 3H),1.0-0.9 (d, 3H); ¹⁹F-NMR (CDCl₃) δ −103.5 (d, 1F), −105.5 (d, 1F); MS(ESI⁺) m/z 471.1 (M+Na).

Step D1: Preparation of5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 24D)

2.9 mg as a colorless oil; TLC R_(f) 0.40 (solvent system: 95:5:1 v/vdichloromethane-methanol-acetic acid); MS (ESI⁺) m/z 457.1 (M+Na).

Step D2: Preparation of5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 24E)

Step D3: Preparation of5-(3-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 24F)

Example 25D5-(3-((R)-3,3-Difluoro-5-((3S,4S,E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid

Example 26D5-(3-((R)-3,3-Difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid

Example 27D5-(3-((R)-3,3-Difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid

Examples 28A-28H Steps A and B: Preparation of methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(28A) and methyl5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 28B)

Methyl5-(3-((R)-3,3-difluoro-5-((S,E)-4-methyl-3-oxo-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewas prepared by the method described in Examples 24, Steps A and B,except that (S)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate(15mb(i)) was used in place of (±)-dimethyl(3-methyl-2-oxooct-5-yn-1-yl)phosphonate (15bb(i)/15bc(i)) in Step A.

Step C: From the stereoisomeric mixture comprising the two-diastereomermixture methyl5-(3-((5R)-3,3-difluoro-5-((4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewere separated the single isomers methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(28A) and methyl5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 28B) by prep HPLC.

Agilent Semi-Prep instrument; ultraviolet detector at 205 nm; LunaSilica 5μ 250 mm×10 mm column; mobile phase of heptane-ethanol (93:7v/v).

Example 28A (3.6 mg); a clear oil; HPLC retention time 12.9-13.6minutes; ¹H-NMR (CDCl₃, 400 MHz) δ 7.6 (d, 1H), 7.3-7.2 (m, 2H), 7.2-7.1(m, 3H), 6.8 (d, 1H), 5.8-5.7 (m, 1H), 5.5-5.4 (m, 1H), 4.1-4.0 (m, 2H),3.85 (s, 3H), 3.7-3.5 (m, 1H), 3.1-3.0 (m, 1H), 2.9-2.8 (t, 2Ht),2.7-2.5 (m, 3H), 2.3-2.1 (m, 1H), 2.0-1.8 (m, 2H), 1.8-1.5 (m, 5H),1.5-1.4 (m, 1H), 1.3-1.2 (m, 1H), 1.2-1.1 (t, 1H), 0.85 (d, 3H); MS(ESI⁺) m/z 528.2 (M+Na).

Example 28B (19.6 mg); a clear oil; HPLC retention time 12.0-12.9minutes; ¹H-NMR (CDCl₃, 400 MHz) δ 7.6 (d, 1H), 7.3-7.2 (m, 2H), 7.2-7.1(m, 3H), 6.8 (d, 1H), 5.8-5.7 (m, 1H), 5.5-5.4 (m, 1H), 4.1-4.0 (m, 2H),3.85 (s, 3H), 3.7-3.5 (m, 1H), 3.1-3.0 (m, 1H), 2.9-2.8 (t, 2H), 2.7-2.5(m, 3H), 2.3-2.1 (m, 1H), 2.0-1.8 (m, 2H), 1.8-1.5 (m, 5H), 1.5-1.4 (m,1H), 1.3-1.2 (m, 1H), 1.2-1.1 (t, 1H), 0.85 (d, 3H); MS (ESI⁺) m/z 528.2(M+Na).

Alternative preparations of Example 28A from methyl5-(3-((R)-3,3-difluoro-5-((S,E)-4-methyl-3-oxo-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Enone intermediate 22f-mb(i)).

Enone 22f-mb(i) was prepared by reacting aldehyde 13f with β-ketophosphonate ester 15mb(i) using a Horner-Wadsworth-Emmons proceduresimilar to the protocol described in Step A for the preparation ofExample 1A above.

Alternative Preparation 1

To a stirring solution consisting of 22f-mb(i) (50 mg, 0.10 mmol) andR)-(+)-2-methyl-CBS-oxazaborolidine (0.12 mL, 0.12 mmol, 1 M in toluene)in dichloromethane (1 mL) was added a solution consisting ofcatecholborane (0.1 mL, 0.1 mmol, 1 M in THF) in dichloromethane (5 mL)over 15 minutes. The reaction was stirred for two hours. The reactionwas quenched with 1 M HCl and extracted with ethyl acetate. The combinedorganic phase was sequentially washed with a 50% saturated aqueoussolution of sodium chloride and a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, filtered, and concentrated toprovide a residue comprising a diastereomeric mixture of Examples 28Aand 28B, which was purified by silica gel chromatography. Elution withmethanol-dichloromethane (1:250 v/v) afforded a purified diastereomericmixture comprising Example 28A and Example 28B (23 mg) as a clear oil;TLC R_(f) 0.50 (solvent system: 97:3 v/v dichloromethane:methanol).

Alternative Preparation 2

A diastereomeric mixture comprising Example 28A and Example 28B, wasprepared by the method as described above in Alternative preparation 1,except 4 molar equivalents of catecholborane (0.4 mL, 0.4 mmol, 1M inTHF) were used instead of 1 molar equivalent to afford a second purifieddiastereomeric mixture comprising Example 28A and Example 28B (70 mg) asa clear oil; TLC R_(f) 0.50 (solvent system: 3:97 v/vdichloromethane-methanol).

Alternative Preparation 3

A diastereomeric mixture comprising Example 28A and Example 28B, wasprepared by the method as described above in Alternative preparation 1,except on a larger scale. The reaction mixture comprising 22f-mb(i) (553mg, 1.1 mmol), (R)-(+)-2-methyl-CBS-oxazaborolidine (1.32 mL, 1.32 mmol,1M in toluene) and catecholborane (1.1 mL, 1.1 mmol, 1 M in THF)afforded a third purified diastereomeric mixture comprising Example 28Aand Example 28B (226 mg) as a clear oil; TLC R_(f) 0.50 (solvent system:3:97 v/v dichloromethane-methanol).

Isolation of single diastereomer Example 28A by separation of a pooledmixture comprising the three purified diastereomeric mixtures generatedfrom the three alternative Example 28A preparations above: The pooledmixture was injected onto the Agilent 1100 prep HPLC; stationary phaseLuna 5m Silica 250×21.2 mm column; mobile phase 96:4 heptane-ethanol;Example 28A eluent collected at retention time 26-29 minutes andconcentrated to afford the single diastereomer Example 28A (110 mg, 17%)as a white solid; TLC R_(f) 0.50 (solvent system: 97:3 v/vdichloromethane:methanol); analytical HPLC, retention time 16.3 min,Agilent 1100 ultraviolet detector at 210 nm, stationary phase,Phenomenex Luna Silica, 5μ, 4.6×250 mm, mobile phase, 95:5heptane-ethanol, flow rate 1 mL/min; ¹H-NMR (CDCl₃) δ 7.6 (d, 1H),7.3-7.2 (m, 2H), 7.2-7.1 (m, 3H), 6.8 (d, 1H), 5.75 (dd, 1H), 5.4 (dd,1H), 4.1-4.0 (m, 2H), 3.82 (s, 3H), 3.6-3.5 (m, 1H), 3.0-2.9 (m, 1H),2.80 (t, 2H), 2.6-2.5 (m, 3H), 2.2-2.1 (m, 1H), 2.1-2.0 (m, 1H), 1.9-1.8(m, 2H), 1.7-1.4 (m, 4H), 1.2-1.1 (m, 1H), 0.84 (d, 3H); ¹⁹F-NMR (CDCl₃,376 Hz) δ −103.6 (ddd, J=270, 15, 3 Hz, 1F), −105.6 (ddd, J=²⁷¹, 17, 15Hz, 1F).

Alternative Preparation 4

To a solution consisting of 22f-mb(i) (10 mg, 0.02 mmol) and (R)-(+)2-methyl-CBS-oxazaborolidine (0.040 mL, 0.040 mmol, 1 M in toluene) indichloromethane (1 mL) was added catecholborane (0.060 mL, 0.060 mmol,1M in THF) in dichloromethane (1 mL) over 15 minutes. The reactionmixture was stirred for two hours and was subsequently quenched with 1 MHCl and extracted with ethyl acetate. The crude product, as a clear oil,was analyzed by HPLC (Phenomenex Luna 5 Silica (2) 4.6×250 mm column at30° C.; mobile phase 95:5:0.1 hexanes-isopropanol-acetic acid):diastereomeric ratio Example 28A-Example 28B=64:36 by area; TLC R_(f)0.50 (solvent system: 3:97 v/v dichloromethane-methanol).

Step D1: Preparation of5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 28C)

TLC R_(f) 0.55 (solvent system: 96:4:1 v/vdichloromethane-methanol-acetic acid); MS (ESI⁻) m/z 490.2 (M−1).

Step D2: Preparation of5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 28D)

TLC R_(f) 0.55 (solvent system: 96:4:1 v/vdichloromethane-methanol-acetic acid); MS (ESI⁻) m/z 490.2 (M−1).

Example 28E and 28F Steps A, B, and C: Preparation of methyl5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 28E) and methyl5-(3-((R)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 28F)

Methyl5-(3-((5R)-3,3-difluoro-5-((4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewas prepared by the method described in Example 28, Steps A and B,except that (R)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate(15mc(i)) was used instead of (S)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) in Step A.

Step C: The pure diastereomers of Example 28E and Example 28F wereisolated following separation by prep HPLC; Gilson Prep HPLC, Lunasilica 5μ 21.2×250 mm, ultraviolet detector 210 nm, mobile phase96:4:0.1 heptane-ethanol-acetic acid, 21.2 ml/min.

Example 28E: 175 mg as a clear oil; TLC R_(f) 0.31 (solvent system:35:65 v/v ethyl acetate-heptane); HPLC retention time 39 min; MS (ESI⁺)m/z 528 (M+Na)⁺; ¹H NMR (CD₃OD) δ 7.62 (d, J=3.66 Hz, 1H), 7.25-7.10 (m,5H), 6.91 (d, J=3.92 Hz, 1H), 5.81 (dd, J=6.23, 15.38 Hz, 1H), 5.42 (dd,J=9.34, 15.20 Hz, 1H), 4.25 (dd, J=4.58, 7.87 Hz, 1H), 3.99-3.89 (m,1H), 3.80 (s, 3H), 3.55-3.47 (m, 1H), 3.34 (s, 1H), 3.16-3.03 (m, 1H),2.85 (dt, J=3.48, 7.42 Hz, 3H), 2.71-2.51 (m, 2H), 2.32-2.19 (m, 1H),1.99-1.85 (m, 2H), 1.71-1.44 (m, 4H), 1.11 (s, 1H), 0.86 (d, J=6.96 Hz,3H); ¹⁹F NMR (CD₃OD) δ −104.4 (ddd, 1F), −107.3 (ddd, 1F); [α]^(T)_(λ)=α/cl, [α]^(21.9) _(D)=−0.004/(0.01568 g/1.5 mL)(0.5)=−0.765°(c=1.045, CHCl₃).

Example 28F: 580 mg as a clear oil; TLC R_(f) 0.31 (solvent system:35:65 v/v ethyl acetate-heptane); HPLC retention time 35 min; MS (ESI⁺)m/z 528 (M+Na)⁺; ¹H NMR (CD₃OD) δ 7.63-7.61 (m, 1H), 7.25-7.10 (m, 5H),6.92 (d, J=3.91 Hz, 1H,), 5.85 (dd, J=5.68, 15.20 Hz, 1H), 5.43 (dd,J=9.34, 15.20 Hz, 1H), 4.29-4.22 (m, 1H), 3.96 (dt, J=1.46, 5.49 Hz,1H), 3.82-3.80 (m, 3H), 3.59-3.47 (m, 1H), 3.36-3.32 (m, 1H), 3.11 (dd,J=6.04, 7.87 Hz, 1H), 2.85 (t, J=7.51 Hz, 2H), 2.79-2.67 (m, 1H), 2.59(t, J=7.51 Hz, 2H), 2.28-2.15 (m, 1H), 1.99-1.86 (m, 2H), 1.75-1.52 (m,3H), 1.47 (td, J=5.17, 13.46 Hz, 1H), 1.17-1.07 (m, 1H), 0.85 (d, J=6.59Hz, 3H); ¹⁹F NMR (CD₃OD) δ −104.5 (ddd, 1F), −107.2 (ddd, 1F).

Alternative preparation of Example 28E from methyl5-(3-((R)-3,3-difluoro-5-((R,E)-4-methyl-3-oxo-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Enone intermediate 22f-mc(i)).

To a solution consisting of methyl5-(3-((R)-3,3-difluoro-5-((R,E)-4-methyl-3-oxo-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(10 mg, 0.02 mmol) and (R)-(+) 2-methyl-CBS-oxazaborolidine (0.040 mL,0.040 mmol, 1 M in toluene) in dichloromethane (1 mL) was addedcatecholborane (0.060 mL, 0.060 mmol, 1M in THF) in dichloromethane (1mL) over 15 minutes. The reaction mixture was stirred for two hours andwas subsequently quenched with 1 M HCl and extracted with ethyl acetate.The crude product, as a clear oil, was analyzed by HPLC (Phenomenex Luna5μ Silica (2) 4.6×250 mm column at 30° C.; mobile phase 95:5:0.1hexanes-isopropanol-acetic acid): diastereomeric ratio Example28E-Example 28F=99:1by area; TLC R_(f) 0.50 (solvent system: 3:97 v/vdichloromethane-methanol).

Enone 22f-mc(i) was prepared by reacting aldehyde 13f with β-ketophosphonate ester 15mc(i) using a Horner-Wadsworth-Emmons proceduresimilar to the protocol described in Step A for the preparation ofExample 1A above.

Step D1: Preparation of5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiphene-2-carboxylicacid (Example 28G)

60 mg (44%) of the title compound as a colorless oil; TLC R_(f) 0.45(solvent system: 60:40:1 v/v/v ethyl acetate-heptane-acetic acid); MS(ESI⁻) m/z 490 (M−H)⁻; ¹H NMR (CD₃OD) δ 7.58 (d, J=4.03 Hz, 1H),7.25-7.10 (m, 5H), 6.89 (d, J=4.02 Hz, 1H), 5.81 (dd, J=6.23, 15.38 Hz,1H), 5.42 (dd, J=9.34, 15.20 Hz, 1H), 4.30-4.21 (m, 1H), 3.93 (t, J=5.49Hz, 1H), 3.62-3.42 (m, 1H), 3.15-3.04 (m, 1H), 2.89-2.68 (m, 4H),2.65-2.51 (m, 2H), 2.32-2.14 (m, 1H), 2.01-1.85 (m, 2H), 1.71-1.44 (m,4H), 1.19-1.05 (m, 1H), 0.92-0.83 (m, 3H); ¹⁹F NMR (CD₃OD) δ −104.3(ddd, 1F), −107.2 (ddd, 1F); [α]^(T) _(λ)=α/cl, [α]^(21.9)_(D)=−0.011/(0.0163 g/1.5 mL)(0.5)=−2.03° (c=1.09, CHCl₃).

Step D2: Preparation of5-(3-((R)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiphene-2-carboxylicacid (Example 28H)

510 mg (94%) of the title compound as a white solid; TLC R_(f) 0.47(solvent system: 50:50:1 v/v/v ethyl acetate-heptane-acetic acid); MP133-134° C.; MS (ESI⁻) m/z 490 (M−H)⁻; ¹H-NMR (CD₃OD) δ 7.58 (d, J=3.66Hz, 1H), 7.26-7.10 (m, 5H), 6.90 (d, J=3.86 Hz, 1H), 5.85 (dd, J=5.49,15.38 Hz, 1H), 5.43 (dd, J=9.15, 15.38 Hz, 1H), 4.30-4.22 (m, 1H), 3.97(dt, J=1.46, 5.49, Hz, 1H), 3.59-3.51 (m, 1H), 3.16-3.07 (m, 1H),2.88-2.67 (m, 4H), 2.59 (t, J=7.51 Hz, 2H), 2.21 (dtd, 1H), 2.00-1.86(m, 2H), 1.76-1.52 (m, 3H), 1.51-1.41 (m, 1H), 1.17-1.07 (m, 1H), 0.86(d, J=6.59 Hz, 3H); ¹⁹F-NMR (CD₃OD) δ −104.5 (ddd, 1F), −107.2 (ddd,1F); [α]^(T) _(λ)=α/cl, [α]^(21.9) _(D)=−0.140/(0.0194 g/2.5mL×0.5)=−36.08° (c=0.776, CHCl₃).

Example 28C—H₂ Preparation of5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 28C—H₂)

To a solution consisting of5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (15.2 mg, 0.031 mmol) in ethanol (12 mL) and covered with anatmosphere of nitrogen was added palladium (12 mg, 10% on activatedcarbon). The nitrogen atmosphere was replaced with hydrogen and thereaction mixture was stirred vigorously for 5 hours at room temperature.The hydrogen was replaced with nitrogen and mixture was filtered througha small pad of celite which was washed with ethanol. The combinedfiltrate was concentrated under vacuum and the residue was purified bysilica gel chromatography eluting with ethyl acetate-heptane-acetic acid(45:55:0.4 v/v/v) to give 9.5 mg (62%) of the title compound as acolorless oil; TLC R_(f) 0.29 (solvent system: 45:55:1 v/v/v ethylacetate-heptane-acetic acid); MS (ESI⁻) m/z 492.2 (M−H)⁻; ¹H NMR (CD₃OD)δ 7.47 (d, J=3.66 Hz, 1H), 7.18-7.01 (m, 5H), 6.80 (d, J=3.30 Hz, 1H),3.72-3.63 (m, 1H), 3.16-3.03 (m, 1H), 2.79 (t, J=7.32 Hz, 2H), 2.61-2.45(m, 3H), 2.19-2.05 (m, 1H), 1.98-1.78 (m, 2H), 1.78-1.57 (m, 2H),1.53-1.39 (m, 4H), 1.34-1.14 (m, 5H), 1.10-1.00 (m, 1H), 0.81-0.76 (m,3H); ¹⁹F NMR (CD₃OD) δ −103.2 (ddd, 1F), −105.9 (ddd, 1F).

Example 29C5-(3-((R)-3,3-Difluoro-5-((S,E)-3-hydroxyoct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid

Example 30C5-(3-((R)-3,3-Difluoro-5-((S,E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid

Example 31C5-(3-((R)-3,3-Difluoro-5-((S,E)-3-hydroxydec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid

Example 32C5-(3-((R)-3,3-Difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid

Examples 33A-33D Steps A, B, and C: Preparation of methyl5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 33A) and methyl5-(3-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 33B)

Methyl5-(3-((5R)-3,3-difluoro-5-((E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewas prepared by the method described in Example 9, Steps A and B, exceptthat (R)-methyl5-(3-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(13f) was used instead of (R)-methyl7-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl) heptanoate (13a).

Step C: From the diastereomeric mixture methyl5-(3-((5R)-3,3-difluoro-5-((E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewere separated the single isomers methyl5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 33A) and methyl5-(3-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 33B) by prep HPLC. The separations were performed on an AgilentSemi-Prep instrument equipped with an ultraviolet detector at 205 nm andusing ultraviolet detector at 205 nm; Luna Silica 5μ 250×10 mm columneluting with a mobile phase of heptanes-ethanol (94:6 v/v).

Example 33A (10.2 mg); a clear oil; prep HPLC retention time 15.9-16.3minutes; ¹H-NMR (CDCl₃) δ 7.6 (d, 1H), 6.8 (d, 1H), 5.9-5.7 (m, 1H),5.5-5.4 (m, 1H), 4.2-4.1 (m, 1H), 4.1-4.0 (m, 1H), 3.9 (s, 3H), 3.7-3.6(m, 1H), 3.2-3.0 (m, 1H), 2.8 (t, 2H), 2.8-2.6 (m, 1H), 2.3-2.1 (m, 1H),2.0-1.8 (m, 2H), 1.8-1.7 (br, 1H), 1.6-1.5 (m, 2H), 1.4-1.2 (m, 6H), 0.9(t, 3H); MS (ESI⁻) m/z 452.0 (M+Na).

Example 33B (24.0 mg); a clear oil; prep HPLC retention time 14.2-14.6minutes; ¹H-NMR (CDCl₃) δ 7.6 (d, 1H), 6.8 (d, 1H), 5.9-5.7 (m, 1H),5.5-5.4 (m, 1H), 4.2-4.1 (m, 1H), 4.1-4.0 (m, 1H), 3.9 (s, 3H), 3.7-3.6(m, 1H), 3.2-3.0 (m, 1H), 2.8 (t, 2H), 2.8-2.6 (m, 1H), 2.3-2.1 (m, 1H),2.0-1.8 (m, 2H), 1.8-1.7 (br, 1H), 1.6-1.5 (m, 2H), 1.4-1.2 (m, 6H), 0.9(t, 3H); MS (ESI⁺) m/z 452.0 (M+Na).

Step D1: Preparation of5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 33C)

10.0 mg of a clear oil; TLC R_(f) 0.40 (solvent system: 90:10:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 7.7 (d, 1H), 6.9(d, 1H), 5.9-5.8 (m, 1H), 5.5-5.4 (m, 1H), 4.2-4.1 (m, 1H), 4.1-4.0 (m,1H), 3.7-3.5 (m, 1H), 3.2-3.0 (m, 1H), 2.9 (t, 2H), 2.8-2.6 (m, 1H),2.3-2.1 (m, 1H), 2.0-1.8 (m, 2H), 1.8-1.0 (m, 9H), 0.8 (t, 3H); MS(ESI⁺) m/z 438.0 (M+Na) (ESI⁻) m/z 414.2 (M−1).

Step D2: Preparation of5-(3-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 33D)

10.0 mg of a clear oil; TLC R_(f) 0.40 (solvent system: 90:10:1 v/vdichloromethane-methanol-acetic acid); ¹H-NMR (CDCl₃) δ 7.7 (d, 1H), 6.9(d, 1H), 5.9-5.8 (m, 1H), 5.5-5.4 (m, 1H), 4.2-4.1 (m, 1H), 4.1-4.0 (m,1H), 3.7-3.5 (m, 1H), 3.2-3.0 (m, 1H), 2.9 (t, 2H), 2.8-2.6 (m, 1H),2.3-2.1 (m, 1H), 2.0-1.8 (m, 2H), 1.8-1.0 (m, 9H), 0.8 (t, 3H); MS(ESI⁺) m/z 438.0 (M+Na) (ESI⁻) m/z 414.2 (M−1).

Example 34C5-(3-((R)-3,3-Difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid

Examples 35A-35D Steps A, B, and C: Preparation of methyl5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 35A) and methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 35B)

Methyl5-(3-((R)-3,3-difluoro-5-((4S,E)-3-hydroxy-4-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewas prepared by the method described in Example 28, Steps A and B,except that (S)-dimethyl (2-oxo-3-phenylbutyl)phosphonate (15jb) wasused instead of (S)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate(15mb(i)) in Step A.

Methyl5-(3-((R)-3,3-difluoro-5-((4S,E)-3-hydroxy-4-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewas prepared by the method described in Example 28, Steps A and B,except that (S)-dimethyl (2-oxo-3-phenylbutyl)phosphonate (15jb) wasused instead of (S)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate(15mb(i)) in Step A.

The pure diastereomers of Example 35A and Example 35B were isolatedfollowing separation by prep HPLC.

Agilent Semi Prep, Chiralpak IA 250×10 mm, ultraviolet detector at 210nm; mobile phase 90:10 heptane-ethanol, flowrate 21.2 mL/min,

Example 35A (peak 2): 4 mg; colorless oil; HPLC retention time 21 min;TLC R_(f) 0.23 (solvent system: 35:65 v/v ethyl acetate-heptane).

Example 35B (peak 1): 9 mg; colorless oil; HPLC retention time 16 min;TLC R_(f) 0.23 (solvent system: 35:65 v/v ethyl acetate-heptane).

Step D1: Preparation of5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 35C)

1.8 mg (46%); colorless oil; TLC R_(f) 0.35(solvent system: 55:45:1 v/vethyl acetate-heptane-acetic acid); MS (ESI⁻) m/z 448.2 (M−H)⁻; ¹H NMR(CD₃OD) δ 7.48 (s, 1H), 7.27-7.16 (m, 5H), 6.84 (s, 1H), 5.85 (dd,J=5.49, 15.38 Hz, 1H), 5.36 (dd, J=9.15, 15.75 Hz, 1H), 3.26-3.11 (m,1H), 2.81-2.58 (m, 5H), 1.93-1.74 (m, 2H), 1.73-1.48 (m, 4H), 0.95-0.85(m, 3H); ¹⁹F NMR (CD₃OD) δ −104.3 (ddd, 1F), −107.2 (ddd, 1F).

Step D2: Preparation of5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 35D)

Example 35D

8.7 mg (100% not pure product); colorless oil; TLC R_(f) 0.35(solventsystem: 55:45:1 v/v ethyl acetate-heptane-acetic acid); MS (ESI⁻) m/z448.2 (M−H)⁻.

Examples 36A-36D Steps A, B, and C: Preparation of methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 36A) and methyl5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 36B)

Methyl5-(3-((5R)-3,3-difluoro-5-((4S,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewas prepared by the method described in Example 28, Steps A and B,except that (S)-dimethyl (3-methyl-2-oxo-4-phenylbutyl)phosphonate(15kb(i)) was used instead of (S)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) in Step A.

Step C: The pure diastereomers of Example 36A and Example 36B wereisolated following separation by prep HPLC; Gilson Prep instrument;ultraviolet detector at 210 nm; Luna silica 5μ 21.2×250 mm column;mobile phase of heptane-ethanol (96:4 v/v), 21.2 mL/min.

Example 36A (39 mg); a clear oil; HPLC retention time 36 min; TLC R_(f)0.18 (solvent system: 35:65 v/v ethyl acetate-heptane); MS (ESI⁺) m/z500 (M+Na)⁺; ¹H-NMR (CD₃OD) δ 7.59 (d, J=4.03H, z1H), 7.27-7.22 (m, 2H),7.19-7.10 (m, 3H), 6.91 (d, J=3.90 Hz, 1H), 5.90 (dd, J=6.41, 15.20 Hz,1H), 5.49 (dd, J=9.34, 15.20 Hz, 1H), 4.30 (tt, J=4.17, 8.28 Hz, 1H),3.96-3.91 (m, 1H), 3.80 (s, 3H), 3.63-3.54 (m, 1H), 3.13 (td, J=6.50,13.37 Hz, 1H), 2.94-2.71 (m, 5H), 2.36-2.23 (m, 2H), 2.05-1.82 (m, 3H),0.76 (d, J=6.96 Hz, 3H); ¹⁹F NMR (CD₃OD) δ −104.4 (ddd, 1F), −107.2(ddd, 1F).

Example 36B (120 mg); a colorless oil; HPLC retention time 34 min; R_(f)0.23 (solvent system: 35:65 v/v ethyl acetate-heptane); MS (ESI⁺) m/z500 (M+Na)⁺; ¹H-NMR (CD₃OD) δ 7.60 (d, J=4.03 Hz, 1H), 7.30-7.20 (m,2H), 7.18-7.13 (m, 3H), 6.91 (d, J=3.50 Hz, 1H), 5.91 (dd, J=4.94, 15.20Hz, 1H), 5.54-5.46 (m, 1H), 4.33-4.26 (m, 1H), 4.05-4.00 (m, 1H), 3.81(s, 3H), 3.63-3.54 (m, 1H), 3.21-3.11 (m, 1H), 2.91-2.70 (m, 5H),2.36-2.21 (m, 2H), 2.05-1.81 (m, 3H), 0.79 (d, J=6.59 Hz, 3H); ¹⁹F NMR(CD₃OD) δ −104.5 (ddd, 1F), −107.2 (ddd, 1F).

Step D1: Preparation of5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 36C)

Example 36C

30 mg (97%), colorless oil; TLC R_(f) 0.23 (solvent system: 50:50:1v/v/v ethyl acetate-heptane-acetic acid; MS (ESI⁻) m/z 462.1 (M−H)⁻; ¹HNMR (CD₃OD) δ 7.56 (d, J=3.66 Hz, 1H), 7.27-7.22 (m, 2H), 7.17-7.12 (m,3H), 6.89 (d, J=4.12, 8.33 Hz, 1H), 5.91 (dd, J=6.23, 15.38 Hz, 1H),5.49 (dd, J=9.34, 15.20 Hz, 1H), 4.30 (tt, J=4.12, 8.33 Hz, 1H), 3.95(dt, J=1.10, 6.04 Hz, 1H), 3.63-3.55 (m, 1H), 3.19-3.09 (m, 1H),2.94-2.61 (m, 5H), 2.36-2.23 (m, 2H), 2.06-1.82 (m, 3H), 0.77 (d, J=6.59Hz, 3H); ¹⁹F NMR (CD₃OD) δ −104.3 (ddd, 1F), −107.2 (ddd, 1F); [α]^(T)_(λ)=α/cl, [α]^(21.9) _(D)=0.025/(0.01501 g/2 mL)(0.5)=+6.66 (c=0.75,CHCl₃).

Step D2: Preparation of5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 36D)

Example 36D

68 mg, colorless oil; TLC R_(f) 0.256 (solvent system: 50:50:1 v/v/vethyl acetate-heptane-acetic acid; MS (ESI⁻) m/z 462.1 (M−H)⁻; ¹H NMR(CD₃OD) δ 7.57 (d, J=3.66 1H, Hz), 7.30-7.20 (m, 2H), 7.18-7.12 (m, 3H),6.89 (d, J=3.91 Hz, 1H), 5.91 (dd, J=4.94, 15.20 Hz, 1H), 5.50 (dd,J=9.34, 15.20 Hz, 1H), 4.33-4.27 (m, 1H), 4.05-4.01 (m, 1H), 3.64-3.55(m, 1H), 3.27-3.12 (m, 1H), 2.91-2.69 (m, 5H), 2.37-2.15 (m, 2H),2.05-1.81 (m, 3H), 0.80 (d, J=6.59 Hz, 3H); ¹⁹F NMR (CD₃OD) δ −104.4(ddd, 1F), −107.2 (ddd, 1F); [α]^(T) _(λ)=α/cl, [α]^(21.9)_(D)=−0.142/(0.01838 g/1.5 mL)(0.5)=−23.17 (c=1.22, CHCl₃).

Examples 37A-37D Steps A, B, and C: Preparation of methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 37A) and methyl5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 37B)

Methyl5-(3-((R)-3,3-difluoro-5-((4S,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewas prepared by the method described in Example 28, Steps A and B,except that (S)-dimethyl (3-methyl-2-oxo-5-phenylpentyl)phosphonate(15lb(i)) was used instead of (S)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) in Step A.

Step C: The pure diastereomers of Example 37A and Example 37B wereisolated following separation by prep HPLC; Gilson Prep instrument;ultraviolet detector at 210 nm; Luna silica 5μ 21.2×250 mm column;mobile phase of heptane-ethanol (96:4 v/v), 21.2 mL/min.

Example 37A (35 mg): as a colorless oil; HPLC retention time 19 min; TLCR_(f) 0.18 (solvent system: 35:65 v/v ethyl acetate-heptane); MS (ESI⁺)m/z 514.2 (M+Na)⁺; ¹H NMR (CD₃OD) δ 7.61 (d, J=3.83 Hz, 1H), 7.25-7.21(m, 2H), 7.17-7.10 (m, 3H), 6.89 (d, J=3.83 Hz, 1H), 5.82 (dd, J=6.59,15.38 Hz, 1H), 5.45 (dd, J=9.34, 15.20 Hz, 1H), 4.95-4.87 (m, 1H), 4.27(tt, J=4.21, 8.24 Hz, 1H), 3.95 (t, J=6.23 Hz, 1H), 3.82 (s, 3H),3.58-3.41 (m, 1H), 3.13-3.04 (m, 1H), 2.90-2.67 (m, 5H), 2.52 (ddd,J=6.59, 9.98, 13.82 Hz, 1H), 2.34-2.24 (m, 1H), 2.00-1.86 (m, 2H),1.79-1.70 (m, 1H), 1.64-1.56 (m, 1H), 1.40-1.23 (m, 1H), 0.91 (d, J=6.59Hz, 3H); ¹⁹F NMR (CD₃OD) δ −104.4 (ddd, 1F), −107.1 (ddd, 1F).

Example 37B (164 mg): colorless oil; HPLC retention time 16 min; TLCR_(f) 0.22 (solvent system: 35:65 v/v ethyl acetate-heptane); MS (ESI⁺)m/z 514.2 (M+Na)⁺; ¹H NMR (CD₃OD) δ 7.61 (d, J=3.66 Hz, 1H), 7.25-7.10(m, 5H), 6.88 (d, J=3.97 Hz, 1H), 5.89 (dd, J=4.94, 15.20 Hz, 1H), 5.47(dd, J=9.34, 15.20 Hz, 1H), 4.32-4.25 (m, 1H), 4.08-4.01 (m, 1H),3.83-3.82 (m, 3H), 3.59-3.47 (m, 1H), 3.12 (dddd, J=1.46, 5.77, 7.87,13.82 Hz, 1H), 2.87-2.65 (m, 5H), 2.61-2.52 (m, 1H), 2.25 (dtd, 1H),2.00-1.75 (m, 3H), 1.59 (dtt, 1H), 1.43-1.32 (m, 1H), 0.95-0.90 (m, 3H);¹⁹F NMR (CD₃OD) δ −104.6 (ddd, 1F), −107.1 (ddd, 1F).

Step D1: Preparation of5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 37C)

Example 37C

21 mg (81%), colorless oil; TLC R_(f) 0.24 (solvent system: 50:50:1v/v/v ethyl acetate-heptane-acetic acid); MS (ESI⁻) m/z 477.56 (M−H)⁻;¹H NMR (CD₃OD) δ 7.57 (d, J=3.66 Hz, 1H), 7.25-7.10 (m, 5H), 6.86 (d,J=3.88 Hz, 1H), 5.88-5.80 (m, 1H), 5.44 (dd, J=9.15, 15.38 Hz, 1H), 4.27(tt, J=4.21, 8.42 Hz, 1H), 3.98-3.93 (m, 1H), 3.59-3.46 (m, 1H),3.13-3.04 (m, 1H), 2.90-2.67 (m, 5H), 2.53 (ddd, J=6.59, 9.80, 13.64 Hz,1H), 2.34-2.21 (m, 1H), 2.03-1.84 (m, 2H), 1.80-1.71 (m, 1H), 1.65-1.55(m, 1H), 1.42-1.28 (m, 1H), 0.92 (d, J=6.59 Hz, 3H); ¹⁹F NMR (CD₃OD) δ−104.5 (ddd, 1F), −107.2 (ddd, 1F); [α]^(T) _(λ)=α/cl, [α]^(21.9)_(D)=−0.049/(0.0158 g/1.5 mL)(0.5)=−9.30 (c=1.05, CHCl₃).

Step D2: Preparation of5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 37D)

64 mg (43%); colorless oil; TLC R_(f) 0.24 (solvent system: 50:50:1v/v/v ethyl acetate-heptane-acetic acid); MS (ESI⁻) m/z 477.56 (M−H)⁻;¹H NMR (CD₃OD) δ 7.58 (d, J=3.66 Hz, 1H), 7.26-7.10 (m, 5H), 6.87 (d,J=3.66 Hz, 1H), 5.89 (dd, J=5.13, 15.38 Hz, 1H), 5.48 (dd, J=9.34, 15.20Hz, 1H), 4.29 (tt, J 4.35, 8.28 Hz, 1H), 4.05 (t, J=4.03 Hz, 1H),3.60-3.52 (m, 1H), 3.17-3.07 (m, 1H), 2.87-2.65 (m, 5H), 2.57 (ddd,J=6.41, 9.89, 13.73 Hz, 1H), 2.32-2.19 (m, 1H), 2.02-1.75 (m, 3H),1.64-1.55 (m, 1H), 1.44-1.32 (m, 1H), 0.97-0.88 (m, 3H); ¹⁹F NMR (CD₃OD)δ −104.4 (ddd, 1F), −107.1 (ddd, 1F); [α]^(T) _(λ)=α/cl, [α]^(21.9)_(D)=−0.170/(0.01556 g/1.5 mL)(0.5)=−32.755 (c=1.04, CHCl₃).

Examples 38A-38D Steps A, B, and C: Preparation of methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 38A) and methyl5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 38B)

Methyl5-(3-((5R)-3,3-difluoro-5-((4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewas prepared by the method described in Example 28, Steps A and B,except that (S)-dimethyl (3-methyl-2-oxo-7-phenylheptyl)phosphonate(15nb(i)) was used instead of (S)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) in Step A.

Step C: The pure diastereomers of Example 38A and Example 38B wereisolated following separation by prep HPLC.

Agilent 1100 Prep instrument; ultraviolet detector at 210 nm; Lunasilica 5μ 21.2×250 mm column; mobile phase of heptane-ethanol (96:4v/v), 21.2 mL/min.

Example 38A (61 mg); a clear oil; HPLC retention time 29 min; R_(f) 0.22(solvent system: 35:65 v/v ethyl acetate-heptane); MS (ESI⁺) m/z 542.2(M+Na)⁺; ¹H NMR (CD₃OD) δ 7.61 (d, J=3.66 Hz, 1H), 7.26-7.19 (m, 2H),7.17-7.10 (m, 3H), 6.91 (d, J=3.66 Hz, 1H), 5.82 (dd, J=6.59, 15.38 Hz,1H), 5.42 (dd, J=9.15, 15.38 1H, Hz), 4.30-4.24 (m, 1H), 3.90 (t, J=6.04Hz, 1H), 3.82 (s, 3H), 3.59-3.47 (m, 1H), 3.16-3.02 (m, 1H), 2.93-2.73(m, 3H), 2.65-2.53 (m, 2H), 2.34-2.20 (m, 1H), 2.02-1.87 (m, 2H),1.62-1.36 (m, 5H), 1.35-1.20 (m, 2H), 1.16-1.04 (m, 1H), 0.81 (d, J=6.59Hz3H); ¹⁹F NMR (CD₃OD) δ −104.4 (ddd, 1F), −107.2 (ddd, 1F).

Example 38B (222 mg); a colorless oil; HPLC retention time 34 min; R_(f)0.26 (solvent system: 35:65 v/v ethyl acetate-heptane); MS (ESI⁺) m/z542.2 (M+Na)⁺; ¹H NMR (CD₃OD) δ 7.62 (d, J=4.03 Hz, 1H), 7.26-7.18 (m,2H), 7.16-7.09 (m, 3H), 6.91 (d, J=3.94 Hz, 1H), 5.88 (dd, J=5.13, 15.38Hz, 1H), 5.46 (dd, J=9.34, 15.56 Hz, 1H), 4.32-4.25 (m, 1H), 4.01-3.96(m, 1H), 3.82 (s, 3H), 3.61-3.53 (m, 1H), 3.17-3.09 (m, 1H), 2.90-2.68(m, 3H), 2.58 (t, J=7.69 Hz, 2H), 2.32-2.18 (m, 1H), 2.02-1.88 (m, 2H),1.64-1.47 (m, 3H), 1.40-1.24 (m, 4H), 1.11-0.99 (m, 1H), 0.84 (d, J=6.96Hz, 3H); ¹⁹F NMR (CD₃OD) δ −104.5 (ddd, 1F), −107.2 (ddd, 1F).

Step D1: Preparation of5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 38C)

28 mg, colorless oil; TLC R_(f) 0.21 (solvent system: 50:50:1 v/v/vethyl acetate-heptane-acetic acid; MS (ESI⁻) m/z 504.1 (M−H)⁻; ¹H NMR(CD₃OD) δ 7.58 (d, J=3.66 Hz, 1H), 7.27-7.09 (m, 5H), 6.89 (d, J=3.99Hz, 1H), 5.84 (dd, J=6.59, 15.01 Hz, 1H), 5.43 (dd, J=9.15, 15.38 Hz,1H), 4.32-4.25 (m, 1H), 3.92 (t, J=6.07 Hz, 1H), 3.61-3.45 (m, 1H),3.17-3.02 (m, 1H), 2.94-2.70 (m, 4H), 2.60 (dt, J=3.84, 7.60 Hz, 2H),2.35-2.21 (m, 1H), 2.05-1.88 (m, 2H), 1.63-1.37 (m, 5H), 1.34-1.22 (m,1H), 1.17-1.04 (m, 1H), 0.83 (d, J=6.59 Hz, 3H); ¹⁹F NMR (CD₃OD) δ−100.5 (ddd, 1F), −103.2 (ddd, 1F); [α]^(T) _(λ)=α/cl, [α]^(21.9)_(D)=−0.032/(0.01617 g/1.5 mL)(0.5)=−5.937 (c=1.08, CHCl₃).

Step D2: Preparation of5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 38D)

170 mg (88%), colorless oil; TLC R_(f) 0.19 (solvent system: 50:50:1v/v/v ethyl acetate-heptane-acetic acid; MS (ESI⁻) m/z 504.1 (M−H)⁻; ¹HNMR (CD₃OD) δ 7.58 (d, J=3.66 Hz, 1H), 7.26-7.18 (m, 2H), 7.16-7.09 (m,3H), 6.89 (d, J=3.66 Hz, 1H), 5.89 (dd, J=5.13, 15.38 Hz, 1H), 5.46 (dd,J=8.79, 15.38 Hz, 1H), 4.29 (tt, J=4.26, 8.38 Hz, 1H), 3.99 (dt, J=1.46,4.76 Hz, 1H), 3.62-3.51 (m, 1H), 3.18-3.09 (m, 1H), 2.92-2.67 (m, 4H),2.58 (t, J=7.69 Hz, 2H), 2.25 (dtd, 1H), 2.03-1.88 (m, 2H), 1.54-1.26(m, 6H), 1.12-0.89 (m, 1H), 0.84 (d, J=6.96 Hz, 3H); ¹⁹F NMR (CD₃OD) δ−104.4 (ddd, 1F), −107.2 (ddd, 1F); [α]^(T) _(λ)=α/cl, [α]^(21.9)_(D)=−0.134/(0.017 g/2 mL)(0.5)=−31.53 (c=0.85, CHCl₃).

Example 39A-39D Steps A, B, and C: Preparation of methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 39A) and methyl5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate(Example 39B)

Methyl5-(3-((R)-3,3-difluoro-5-((4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylatewas prepared by the method described in Example 28, Steps A and B,except that (S)-dimethyl (3-methyl-2-oxo-8-phenyloctyl)phosphonate(15ob(i)) was used instead of (S)-dimethyl(3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) in Step A.

Step C: The pure diastereomers of Example 39A and Example 39B wereisolated following separation by prep HPLC.

Gilson Prep instrument; ultraviolet detector at 210 nm; Luna silica 5μ21.2×250 mm column; mobile phase of heptane-ethanol (96:4 v/v), 21.2mL/min.

Example 39A: 46 mg; colorless oil; HPLC retention time 22.5 min; TLCR_(f) 0.24 (solvent system: 35:65 v/v ethyl acetate-heptane); MS (ESI⁺)m/z 556.2 (M+Na)⁺; ¹H NMR (CD₃OD) δ 7.62 (d, J=3.66 Hz, 1H), 7.25-7.19(m, 2H), 7.16-7.10 (m, 3H), 6.90 (d, J=3.86 Hz, 1H), 5.82 (dd, J=6.59,15.38 Hz, 1H), 5.44 (dd, J=9.15, 15.38 Hz, 1H), 4.30-4.24 (m, 1H),3.93-3.89 (m, 1H), 3.82 (s, 3H), 3.58-3.47 (m, 1H), 3.13-3.05 (m, 1H),2.91-2.73 (m, 3H), 2.58 (t, J=7.51 Hz, 2H), 2.27 (dtd, 1H), 2.01-1.87(m, 2H), 1.64-1.51 (m, 3H), 1.44-1.21 (m, 6H), 1.03 (q, J=9.03 Hz, 1H),0.82 (d, J=6.96 Hz, 3H); ¹⁹F NMR (CD₃OD) δ −104.4 (ddd, 1F), −107.2(ddd, 1F).

Example 39B: 211 mg; colorless oil; HPLC retention time 19 min; TLCR_(f) 0.27 (solvent system: 35:65 v/v ethyl acetate-heptane); MS (ESI⁺)m/z 556.2 (M+Na)⁺.

Step D1: Preparation of5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 39C)

3 mg (8%); colorless oil; TLC R_(f) 0.13 (solvent system: 50:50:1 v/v/vethyl acetate-heptane-acetic acid; MS (ESI⁻) m/z 518.2 (M−H)⁻; ¹H NMR(CD₃OD) δ 7.51 (d, J=3.66 Hz, 1H), 7.28-7.18 (m, 2H), 7.17-7.08 (m, 3H),6.84 (d, J=3.66 Hz, 1H), 5.83 (dd, J=6.59, 15.38 Hz, 1H), 5.44 (dd,J=9.15, 15.38 Hz, 1H), 4.27 (tt, J=4.17, 8.47 Hz, 1H), 3.91 (t, J=6.04Hz, 1H), 3.57-3.43 (m, 1H), 3.17-2.99 (m, 1H), 2.89-2.71 (m, 3H),2.65-2.51 (m, 2H), 2.29-2.19 (m, 1H), 2.03-1.88 (m, 2H), 1.36-1.20 (m,9H), 1.12-1.01 (m, 1H), 0.89-0.82 (m, 3H); ¹⁹F NMR (CD₃OD) δ −104.4(ddd, 1F), −107.2 (ddd, 1F).

Step D2: Preparation of5-(3-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid (Example 39D)

90 mg (46%); colorless oil; TLC R_(f) 0.2 (solvent system: 50:50:1 v/v/vethyl acetate-heptane-acetic acid; MS (ESI⁻) m/z 518.2 (M−H)⁻; [α]^(T)_(λ)=α/cl, [α]^(21.9) _(D)=−0.177/(0.026 g/2 mL)(0.5)=−27.23° (c=1.3,CHCl₃).

Example 92 Radioligand Binding Assay for the Evaluation of the Affinityof Compounds for the Agonist Site of the Human Prostanoid EP₄ Receptorin Transfected HEK-293 Cells

Assay volume and format: 200 μl in 96-well plate

Cell membrane homogenates (20 μg protein) are incubated for 120 min at22° C. with 0.5 nM [³H]PGE₂ in the absence or presence of the testcompound in a buffer containing 10 mM MES/KOH (pH 6.0), 10 mM MgCl₂ and1 mM EDTA.

Nonspecific binding is determined in the presence of 10 μM PGE₂.

Following incubation, the samples are filtered rapidly under vacuumthrough glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI andrinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cellharvester (Unifilter, Packard). The filters are dried then counted forradioactivity in a scintillation counter (Topcount, Packard) using ascintillation cocktail (Microscint 0, Packard).

The standard reference compound is PGE₂, which is tested in eachexperiment at several concentrations to obtain a competition curve fromwhich its IC₅₀ is calculated.

Example 93 Functional Cellular Assays (STEP Plate Format)

Both SEAP activity assay and cAMP level assay for EP₂ or EP₄ agonistwere performed on EP₂/EP₄ STEP (Surface Transfection and ExpressionProtocol) plates (from Originus®) which are coated with both rat EP₂ orEP₄ receptor and secreted alkaline phosphatase (SEAP) reporterconstructs. Cells grown on the STEP complex will express EP₂ or EP₄ atthe cell surface. Binding of agonists to EP₂ or EP₄ initiates a signaltransduction cascade results in a transient increase in cAMP and anincrease in expression of SEAP which is secreted into the cell culturemedia. cAMP levels were then measured with an ELISA assay and SEAPactivity was measured with a luminescence-based alkaline phosphatasesubstrate.

Procedure of SEAP Activity Assay for EP₂/EP₄ Agonist

1. Seed cells on an EP₂ or EP₄ STEP plate at a density of 40,000-80,000cells/well in 200 μl of reduced serum medium containing 0.5% FBS. Placethe plate in a 37° C. incubator with 5% CO₂ and incubate overnight.

2. After 16-18 hours of incubation, aspirate the culture media from eachwell.

3. Add 200 μl of culture medium containing different concentration oftest compounds to the assigned wells. For each test compound, at least 8concentrations starting at highest 10 μM and lowest 0.01 pM were tested.In addition each concentration had triplicates. A PGE₂ curve(concentrations from lowest to highest, 0 pM, 0.384 pM, 1.92 pM, 9.6 pM,48 pM, 240 pM, 1200 pM, and 6000 pM) was always run in parallel withtest compounds.

4. After 6-8 hours of stimulation with test compounds and PGE₂, 10 μl ofculture media from each well was transferred to a corresponding well ofa 96-well solid black plate. Cover the plate with the lid.

5. Inactivate the endogenous alkaline phosphatase by heating the samplesat 65° C. for 30 minutes.

6. Add 50 μl of luminescence-based alkaline phosphatase substrate(Michigan Diagnostics, LLC, Cat#SAP450101) to each well.

7. Measure the SEAP activity by reading the luminescent signal from eachwell.

8. The data was analyzed and the EC₅₀ for PGE₂ and each test compoundwas calculated using GraphPad Prism 5.

Procedure of cAMP Assay for EP₂/EP₄ Agonist

1. Seed cells on an EP₂ or EP₄ STEP plate at a density of 40,000-80,000cells/well in 200 μL of reduced serum medium containing 0.5% FBS. Placethe plate in a 37° C. incubator with 5% CO₂ and incubate overnight.

2. After 16-18 hours of incubation, aspirate the culture media from eachwell.

3. Add 200 μl of culture medium containing 500 μM IBMX (an inhibitor ofcAMP phosphodiesterase) and different concentration of test compounds tothe assigned wells. For each test compound, at least 8 concentrationsstarting at highest 10 μM and lowest 0.01 pM were tested. In additioneach concentration had triplicates. A PGE₂ curve (concentrations fromlowest to highest, 0 pM, 0.384 pM, 1.92 pM, 9.6 pM, 48 pM, 240 pM, 1200pM, and 6000 pM) was always run in parallel with test compounds.

4. Incubate the cells in a cell culture incubator for 30 minutes.

5. Centrifuge the plate at 1,000×rpm for 10 minutes.

6. Aspirate the supernatant.

7. Add 100 μL of EIA assay buffer to each well and put the plate withthe lid in a −80° C. freezer. Freeze the sample in the −80° C. for atleast one hour.

8. Take the plate out from the −80° C. freezer and leave it at roomtemperature to thaw completely.

9. Centrifuge the plate at 1,000×rpm for 10 minutes.

10. Pick up 50 μl of supernatant from each well for cAMP levelmeasurement, using an ELISA assay kit from Cayman chemical, Item#581001.

11. The data was analyzed and the EC₅₀ for PGE₂ and each test compoundwas calculated using GraphPad Prism 5.

Specificity of EP₂/EP₄ Agonist on the Receptors

Compounds demonstrating potency in SEAP or cAMP functional assays wereconfirmed for receptor agonist specificity by incubation of the cellswith the compound together with an EP₂ specific antagonist AH-6809 or anEP₄ specific antagonist L-161,982. Compounds that showed agonistactivity for either EP₂ or EP₄ are specific if the stimulation effectwas diminished when incubated together with their receptor specificantagonist.

TABLE 1

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ PGE₂ 0.38 ± 0.07 0.14 ± 0.02 0.48 ± 0.36 0.05 ± 0.0359 ± 17 (N = 10) (N = 10) (N = 22) (N = 38) (N = 15) PGE₁ 0.22 ± 0.0416.5 (N = 5) 1A α β Me 1B α α Me 1C β α/β Me 1D β β Me 1E β α Me 1F α βH 1.2 0.44 0.15 0.059 1G α α H 1H β β H 1I β α H

TABLE 2

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 2A α β Me 2B β β Me 2C α β H 1.3 0.49 0.24 ± 0.080.038 ± 0.037 >1,000 (N = 11) (N = 4) 2D β β H

TABLE 3

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 3A α β Me 3B α α Me 3C β α/β Me 3D β β Me 3E β α Me 3Fα β H 3G α α H 3H β β H 3I β α H

TABLE 4

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 4A α β Me 4B α α Me 4C β α/β Me 4D β β Me 4E β α Me 4Fα β H 4G α α H 4H β β H 4I β α H

TABLE 5

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 5A α β Me 5B α α Me 5C β α/β Me 5D β β Me 5E β α Me 5Fα β H 5G α α H 5H β β H 5I β α H

TABLE 6

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 6A α β Me 6B α α Me 6C β α/β Me 6D α β H 2.4 0.890.023 ± 0.019 <0.001 >1,000 (N = 9) 6E α α H 6F β α/β H

TABLE 7

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 7A α Me 7B β Me 7C α H 7D β H

TABLE 8

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 8A α Me 8B β Me 8C α H 8D β H

TABLE 9

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 9A α Me 9B β Me 9C α H 0.57 0.21 0.37 0.059 205 ± 124 (N = 2)9D β H

TABLE 10

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 10A α Me 10B β Me 10C α H 4.9 1.8 1.10 0.010 10D β H

TABLE 11

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 11A α β Me 11B α α Me 11C β α/β Me 11D α β H 11E α α H11F β α/β H

TABLE 12

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 12A α β Me 12B α α Me 12C β α/β Me 12D α β H 0.32 0.120.047 0.035 1,630 12E α α H 12F β α/β H

TABLE 13

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 13A α β Me 13B α α Me 13C β α/β Me 13D α β H 13E α α H13F β α/β H

TABLE 14

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 14A α β Me 14B α α Me 14C β α/β Me 14D α β H 14E α α H14F β α/β H

TABLE 15

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 15A α β Me 15B α α Me 15C β α/β Me 15D α β H 15E α α H15F β α/β H

TABLE 16

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 16A α β Me 16B α α Me 16C β α/β Me 16D α β H 16E α α H16F β α/β H

TABLE 17

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 17A α Me 17B β Me 17C α H 17D β H

TABLE 18

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 18A α Me 18B β Me 18C α H 18D β H

TABLE 19

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 19A α Me 19B β Me 19C α H 19D β H

TABLE 20

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 20A α Me 20B β Me 20C α H 20D β H

TABLE 21

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 21A α Me 21B β Me 21C α H 0.22 0.082 0.61 0.075 1,960 21D β H

TABLE 22

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 22A α Me 22B β Me 22C α H 22D β H

TABLE 23

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 23A α β Me 23B α α Me 23C β α/β Me 23D α β H 23E α α H23F β α/β H

TABLE 24

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 24A α β Me 24B α α Me 24C β α/β Me 24D α β H 3.3 1.20.73 ± 0.31 0.11 763 (N = 6) 24E α α H 24F β α/β H

TABLE 25

hEP₄ receptor Absolute Configuration binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 25A α β Me 25B α α Me 25C β α/β Me 25D α β H 25E α α H25F β α/β H

TABLE 26

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 26A α β Me 26B α α Me 26C β α/β Me 26D α β H 26E α α H26F β α/β H

TABLE 27

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 27A α β Me 27B α α Me 27C β α/β Me 27D α β H 27E α α H27F β α/β H

TABLE 28

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 28A α β Me 28B β β Me 28C α β H 0.74 0.28 0.010 ±0.021 148 ± 5 (N = 10) (N = 2) 28D β β H 5.68 28E α α Me 50.8 28F β αMe >1,000 28G α α H 0.0162 65 28H β α H 3.15

TABLE 28C-H₂

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ cAMP/EP₂ 28C-H₂ α β H 0.0029 ± 0.0008 1,310 (N = 2)

TABLE 29

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 29A α Me 29B β Me 29C α H 29D β H

TABLE 30

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 30A α Me 30B β Me 30C α H 30D β H

TABLE 31

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 31A α Me 31B β Me 31C α H 31D β H

TABLE 32

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 32A α Me 32B β Me 32C α H 32D β H

TABLE 33

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄SEAP/EP₂ 33A α Me 33B β Me 33C α H 0.28 0.10 0.079 0.063 326 33D β H

TABLE 34

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄ SEAP/EP₄34A α Me 34B β Me 34C α H 34D β H

TABLE 35

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 35A α β Me 35B β β Me 35C α β H 62 35D β β H

TABLE 36

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 36A α β Me 5.02 36B β β Me >1,000 36C α β H 0.0381,000 36D β β H

TABLE 37

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 37A α β Me 8.09 37B β β Me 37C α β H 0.15 37D β β H198 743

TABLE 38

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 38A α β Me >1,000 38B β β Me >1,000 38C α β H0.00000014 157 38D β β H 0.37 >10,000

TABLE 39

Absolute Configuration hEP₄ receptor binding STEP cell functional assayEC₅₀s (nM) Example No. C-15 C-16 R¹⁰ IC₅₀ (nM) K_(i) (nM) cAMP/EP₄SEAP/EP₄ SEAP/EP₂ 39A α β Me >1,000 39B β β Me >1,000 39C α β H0.0000027 1,020 39D β β H 0.059 79,000

Example 94 Accelerated Healing of a Calvarial Bone Defect by EXAMPLE 2C

The rat calvarial defect model is a widely used model through which theability of a treatment agent to induce bone formation is assessed(Aghaloo et al., The effect of NELL1 and bone morphogenetic protein-2 oncalvarial bone regeneration, J. Oral Maxillofac. Surg. 2010: 68:300-308;Mark et al., Repair of calvarial nonunions by osteogenin, abone-inductive protein, Plast. Reconstr. Surg. 1990: 86:623-30).

Bone defects are created by removal of bone from the cranium of femaleSprague Dawley rats by a bone trephine (cranial defect). Cranial defectsare 2.6 mm in diameter and the cranium approximately 1 mm thick. Amatrix of approximately 2 mm thickness is applied to the defect. Thusthe dosing volume for each defect is calculated as π*r²*matrixthickness=3.14*1.3²*2=10.61 μl and rounded to 11 μl for purposes of dosecalculation.

EXAMPLE 2C is delivered set inside calcium phosphate cement that, afterloading with drug and setting, is ground to a fine powder and suspendedin demineralized bone matrix at a ratio of 1:8 (weight/volume). EXAMPLE2C is tested at seven doses with five rats in each group. These are 3,10, 30, 100 and 300 μg/ml and 1 and 3 mg/ml. A negative control grouptreated with dosing matrix containing no drug (Vehicle) as well as apositive control group treated with 50 μg/ml recombinant human bonemorphogenetic protein 2 (BMP-2) are also included in the study.

Calcium Phosphate cement powders may be combinations of α-tri-Calciumphosphate, β-tri-Calcium phosphate and hydroxyapatite; combinations ofDicalcium Phosphate and Tetracalcium Phosphate; or a commerciallyavailable calcium phosphate cement. Commercially available Humandemineralized bone matrix, Puros Demineralized Bone Matrix Puttymanufactured by RTI Biologics (Alachua, Fla.) using the Urist & Dowellmethod, is used in the studies described. Demineralized bone matrix canalso be made by the method described by Urist & Dowell (InductiveSubstratum for Osteogenesis in Pellets of Particulate Bone Matrix, Clin.Orthop. Relat. Res., 1968, 61, 61-78.)

Dosing solutions are made from a 5 mg/ml EXAMPLE 2C stock which is madeby dissolving 1.5 mg of neat EXAMPLE 2C in 300 μl of 100% ethanol.

The dosing volume of a single defect is 11 μl. Thus for each group offive rats the total treatment volume is 55 μl. The ratio of calciumphosphate cement to volume is 1:8 thus for each group of five rats 6.8mg of calcium phosphate cement was used.

The dosing solutions were made up by adding 5 mg/ml Example 2C dissolvedin ethanol onto 6.8 mg of calcium phosphate cement using the volumesshown in the table below. The 10 μg/ml dose and the 3 μg/ml dose werenot made directly from the 5 mg/ml stock but were made with 5.5 μl of afurther 1:50 dilution of the stock and 3.3 μl of a 1:100 stock dilutionrespectively.

mg/defect = μl of 5 mg/ml Dose * mg/group = stock/group = (11/1000)(mg/defect) * 5 (mg/group)/(5/1000) Vehicle 0 0 0 BMP-2 0 0 0 3 mg/ml0.033 0.165 33 1 mg/ml 0.011 0.055 11 300 μg/ml 0.0033 0.0165 3.3 100μg/ml 0.0011 0.0055 1.1 30 μg/ml 0.00033 0.00165 0.33 10 μg/ml 0.000110.00055 5.5 μl of 1:50 stock dilution in ethanol 3 μg/ml 0.0000330.000165 3.3 μl of 1:100 stock dilution in ethanol

After the ethanol has been vented off, the cement is wetted with asetting solution and mixed thoroughly for 1 minute as the cement beginsto set. Calcium phosphate cement containing no Example 2C is also madeup for the Vehicle and BMP-2 groups. The cement-drug mixture is allowedto set overnight at room temperature before being ground to a finepowder in a mortar and pestle.

Following grinding the cement is added to 55 μl of demineralized bonematrix (DBM) and thoroughly mixed using two spatulas. The cement-DBM mixis rolled into a single length of material of equal thickness and usinga ruler as a guide cut into five equal length pieces. The dosing matrixis placed in a test subject within four hours of mixing the cement withthe DBM.

Immediately after creation the bone defect is filled with dosing matrixcontaining either no drug, 50 μg/ml BMP-2 or a defined concentration ofExample 2C. The operation area is closed and sutured and the animalallowed to recover. Eight weeks after the beginning of treatment eachrat is anaesthetized with isoflurane and the defect area is imaged usinga cone beam dental CT scanner (Vatech Pax-Duo3D).

The area measured each week is compared to that of the first week andthe degree of repair calculated by the following formula:

(original area−current area)/original area*100

The mean repair for each group after eight weeks of treatment is shownin the FIG. 1.

The above description of the examples and embodiments of the inventionis merely exemplary in nature and, thus, variations thereof are not tobe regarded as a departure from the spirit and scope of the invention.

1. A method of treating osteoporosis, bone fracture, bone loss, orincreasing bone density comprising administering to a patient in needthereof a therapeutically effective amount of a compound of formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein: L¹ is a)C₃-C₇alkylene, C₃-C₇alkenylene, or C₃-C₇alkynylene, wherein theC₃-C₇alkylene, C₃-C₇alkenylene, or C₃-C₇alkynylene are each optionallysubstituted with 1, 2, 3, or 4 fluoro substituents; b)—(CH₂)_(t)-G-(CH₂)_(p)—; wherein t is 0, 1, or 2, p is 0, 1, 2, or 3,and t+p=0, 1, 2, 3, or 4; or c) —(CH₂)_(n)-G¹-(CH₂)_(p)—,—(CH₂)_(n)-G²-(CH₂)_(p)—, —(CH₂)_(n)—C≡C-G²-, or—(CH₂)_(n)—C(R¹³)═C(R³)-G²-, wherein n is 1, 2, 3, 4, or 5, p is 0, 1,2, or 3, and n+p=1, 2, 3, 4, 5, or 6; G is

G¹ is O, C(O), S, S(O), S(O)₂, or NR⁸; wherein R⁸ is H, C₁-C₄ alkyl, orC₁-C₄alkylcarbonyl; G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; R¹ is COOR¹⁰, CONR¹⁰R¹¹,CH₂OR¹⁰, SO₃R¹⁰, SO₂NR¹⁰R¹¹, PO(OR¹⁰)₂, or tetrazol-5-yl; R¹⁰ is H,C₁-C₄ alkyl, or aryl; R¹¹ is H, C₁-C₄ alkyl, COR¹², OR¹⁰, or SO₂R¹²; R¹²is C₁-C₄ alkyl; R¹³, at each occurrence, is independently H orC₁-C₄alkyl; L⁴ is —C(R²)₂—C(R³)₂—, —C(R²)═C(R³)—, —C≡C—, or

wherein R² and R³ are each H, CH₃, fluoro, or choro; L² is —CH₂— or abond; R⁴ and R⁵ are each independently H, F, CF₃, or C₁-C₄ alkyl; or R⁴and R⁵ together with the carbon to which they are attached form aC₃-C₅cycloalkyl,

R⁶ is aryl, heteroaryl, C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, C₃-C₁₀haloalkynyl, or L³-R⁷; whereinthe aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₄alkyl,C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy; and—C₁-C₃alkylene-C₁-C₃alkoxy; and wherein the C₃-C₁₀alkyl, C₃-C₁₀alkenyl,C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, and C₃-C₁₀haloalkynylare optionally substituted with a substituent selected from the groupconsisting of COOR^(10′), CONR^(10′)R^(11′), CH₂OR^(10′), SO₃R^(10′),SO₂NR^(10′)R^(11′), PO(OR^(10′))₂, and tetrazol-5-yl; R^(10′) is H,C₁-C₄ alkyl, or aryl; R^(11′) is H, C₁-C₄ alkyl, COR^(12′), OR^(10′), orSO₂R^(12′); R^(12′) is C₁-C₄ alkyl; L³ is C₁-C₆alkylene,C₂-C₆alkenylene, C₂-C₆alkynylene, —(CH₂)_(m)-G³-(CH₂)_(q)—,—(CH₂)_(m)-G⁴-(CH₂)_(q)—, or -G⁵-C≡C—; wherein the C₁-C₆alkylene,C₂-C₆alkenylene, and C₂-C₆alkynylene are optionally substituted with 1,2, 3, or 4 fluoro substituents; and wherein m and q are eachindependently 0, 1, 2, or 3 and m+q=0, 1, 2, 3, or 4; G³ is O, C(O), S,S(O), S(O)₂, or NR⁹; wherein R⁹ is H, C₁-C₄ alkyl, orC₁-C₄alkylcarbonyl; G⁴ is

wherein G⁴ is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; G⁵ is

wherein G⁵ is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; R⁷ is C₃-C₈cycloalkyl, aryl,heteroaryl, or heterocyclyl; wherein R⁷ is optionally substituted with1, 2, 3, or 4 substituents selected from the group consisting ofC₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy; r is 0 or 1; and s is 0or
 1. 2. The method of claim 1, wherein: L¹ is a) C₃-C₇alkylene, whereinthe C₃-C₇alkylene is optionally substituted with 1, 2, 3, or 4 fluorosubstituents; or c) —(CH₂)_(n)-G²-(CH₂)_(p)—, —(CH₂)_(n)—C≡C-G²-, or—(CH₂)_(n)—C(H)═C(H)-G²-, wherein n is 1, 2, 3, 4, or 5, p is 0, 1, 2,or 3, and n+p=1, 2, 3, 4, 5, or 6; G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; R¹ is COOR¹⁰; and R¹⁰ is H orC₁-C₄ alkyl.
 3. The method of claim 1, wherein:

L⁴ is —C(R²)═C(R³)—; R² and R³ are each hydrogen; R⁴ and R⁵ areindependently H or C₁-C₄ alkyl; R⁶ is C₃-C₁₀alkyl, C₃-C₁₀alkynyl, orL³-R⁷; L³ is C₁-C₆alkylene or C₂-C₆alkynylene; wherein the C₁-C₆alkyleneand C₂-C₆alkynylene are optionally substituted with 1, 2, 3, or 4 fluorosubstituents; and R⁷ is aryl, wherein R⁷ is optionally substituted with1, 2, 3, or 4 substituents selected from the group consisting ofC₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy.
 4. The method of claim2, wherein:

L⁴ is —C(R²)₂—C(R³)₂—, —C(R²)═C(R³)—, —C≡C—, or

wherein R² and R³ are each H, CH₃, fluoro, or chloro; R⁴ and R⁵ are eachindependently H, F, CF₃, or C₁-C₄ alkyl; or R⁴ and R⁵ together with thecarbon to which they are attached form a C₃-C₅ cycloalkyl; R⁶ is aryl,C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl,C₃-C₁₀haloalkenyl, C₃-C₁₀haloalkynyl, or L³-R⁷; L³ is C₁-C₆alkylene,C₂-C₆alkenylene, or C₂-C₆alkynylene wherein the C₁-C₆alkylene,C₂-C₆alkenylene, and C₂-C₆alkynylene are optionally substituted with 1,2, 3, or 4 fluoro substituents; and R⁷ is aryl, wherein R⁷ is optionallysubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy.
 5. The method of claim4, wherein: L⁴ is

R⁴ and R⁵ are independently H or C₁-C₄ alkyl; R⁶ is C₃-C₁₀alkyl,C₃-C₁₀alkenyl, C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl,C₃-C₁₀haloalkynyl, or L³-R⁷; L³ is C₁-C₆alkylene, C₂-C₆alkenylene, orC₂-C₆alkynylene; wherein the C₁-C₆alkylene, C₂-C₆alkenylene, andC₂-C₆alkynylene are optionally substituted with 1, 2, 3, or 4 fluorosubstituents; and R⁷ is aryl, wherein R⁷ is optionally substituted with1, 2, 3, or 4 substituents selected from the group consisting ofC₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy.
 6. The method of claim5, wherein: R⁴ and R⁵ are independently H or CH₃; R⁶ is C₃-C₁₀alkyl,C₃-C₁₀alkynyl, or L³-R⁷; L³ is C₁-C₆alkylene or C₂-C₆alkynylene; whereinthe C₁-C₆alkylene and C₂-C₆alkynylene are optionally substituted with 1,2, 3, or 4 fluoro substituents; and R⁷ is aryl, wherein R⁷ is optionallysubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy.
 7. The method of claim6, wherein: L¹ is a) C₃-C₇alkylene; or c) —(CH₂)_(n)-G²-, wherein n is 2or 3; G² is

R⁶ is propyl, butyl, pentyl, propynyl, butynyl, pentynyl, hexynyl, orL³-R⁷; L³ is propylene, butylene, pentylene, propynylene, or butynylene;and R⁷ is phenyl.
 8. The method of claim 7, wherein: L¹ is a)n-hexylene; or c) —(CH₂)_(n)-G²-, wherein n is 2 or 3; G² is

R¹ is COOR¹⁰; R¹⁰ is H or CH₃; R⁶ is n-butyl, but-2-yn-1-yl,pent-2-yn-1-yl, hex-2-yn-1-yl, or L³-R⁷; L³ is n-propylene, n-butylene,n-pentylene, or —CH₂—C≡C—; and R⁷ is phenyl.
 9. The method of claim 5,wherein: R⁶ is C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, or C₃-C₁₀haloalkynyl.
 10. The methodof claim 5, wherein: R⁶ is L³-R⁷; L³ is C₁-C₆alkylene, C₂-C₆alkenylene,or C₂-C₆alkynylene; wherein the C₁-C₆alkylene, C₂-C₆alkenylene, andC₂-C₆alkynylene are optionally substituted with 1, 2, 3, or 4 fluorosubstituents; and R⁷ is aryl, wherein R⁷ is optionally substituted with1, 2, 3, or 4 substituents selected from the group consisting ofC₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy.
 11. The method of claim5, wherein: L¹ is C₃-C₇alkylene, wherein the C₃-C₇alkylene is optionallysubstituted with 1, 2, 3, or 4 fluoro substituents.
 12. The method ofclaim 5, wherein: L¹ is —(CH₂)_(n)-G²-(CH₂)_(p)—, —(CH₂)_(n)—C≡C-G²-, or—(CH₂)_(n)—C(H)═C(H)-G²-, wherein n is 1, 2, 3, 4, or 5, p is 0, 1, 2,or 3, and n+p=1, 2, 3, 4, 5, or 6; and G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy.
 13. The method of claim 9,wherein: L¹ is C₃-C₇alkylene, wherein the C₃-C₇alkylene is optionallysubstituted with 1, 2, 3, or 4 fluoro substituents.
 14. The method ofclaim 9, wherein: L¹ is —(CH₂)_(n)-G²-(CH₂)_(p)—, —(CH₂)_(n)—C≡C-G²-, or—(CH₂)_(n)—C(H)═C(H)-G²-, wherein n is 1, 2, 3, 4, or 5, p is 0, 1, 2,or 3, and n+p=1, 2, 3, 4, 5, or 6; and G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy.
 15. The method of claim 10,wherein: L¹ is C₃-C₇alkylene, wherein the alkylene is optionallysubstituted with 1, 2, 3, or 4 fluoro substituents.
 16. The method ofclaim 10, wherein: L¹ is —(CH₂)_(n)-G²-(CH₂)_(p)—, —(CH₂)_(n)—C≡C-G²-,or —(CH₂)_(n)—C(H)═C(H)-G²-, wherein n is 1, 2, 3, 4, or 5, p is 0, 1,2, or 3, and n+p=1, 2, 3, 4, 5, or 6; and G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy.
 17. The method of claim 1comprising administering a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein:

L¹ is a) C₃-C₇alkylene, C₃-C₇alkenylene, or C₃-C₇alkynylene, wherein theC₃-C₇alkylene, C₃-C₇alkenylene, or C₃-C₇alkynylene are each optionallysubstituted with 1, 2, 3, or 4 fluoro substituents; b)—(CH₂)_(t)-G-(CH₂)_(p)—; wherein t is 0, 1, or 2, p is 0, 1, 2, or 3,and t+p=0, 1, 2, 3, or 4; or c) —(CH₂)_(n)-G¹-(CH₂)_(p)—,—(CH₂)_(n)-G²-(CH₂)_(p)—, —(CH₂)_(n)—C≡C-G²-, or—(CH₂)_(n)—C(R¹³)═C(R¹³)-G²-, wherein n is 1, 2, 3, 4, or 5, p is 0, 1,2, or 3, and n+p=1, 2, 3, 4, 5, or 6; G is

G¹ is O, C(O), S, S(O), S(O)₂, or NR⁸; wherein R⁸ is H, C₁-C₄ alkyl, orC₁-C₄alkylcarbonyl; G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; R¹ is COOR¹⁰, CONR¹⁰R¹¹,CH₂OR¹⁰, SO₃R¹⁰, SO₂NR¹⁰R¹¹, PO(OR¹⁰)₂, or tetrazol-5-yl; R¹⁰ is H,C₁-C₄ alkyl, or aryl; R¹¹ is H, C₁-C₄ alkyl, COR¹², OR¹⁰, or SO₂R¹²; R¹²is C₁-C₄ alkyl; R¹³, at each occurrence, is independently H orC₁-C₄alkyl; R⁴ and R⁵ are each independently H, F, CF₃, or C₁-C₄ alkyl;or R⁴ and R⁵ together with the carbon to which they are attached form aC₃-C₅ cycloalkyl,

R⁶ is aryl, heteroaryl, C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, C₃-C₁₀haloalkynyl, or L³-R⁷; whereinthe aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₄alkyl,C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy; and—C₁-C₃alkylene-C₁-C₃alkoxy; and wherein the C₃-C₁₀alkyl, C₃-C₁₀alkenyl,C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, and C₃-C₁₀haloalkynylare optionally substituted with a substituent selected from the groupconsisting of COOR¹⁰, CONR¹⁰R¹¹, CH₂OR¹⁰, SO₃R¹⁰, SO₂NR¹⁰R¹¹, PO(OR¹⁰)₂,and tetrazol-5-yl; L³ is C₁-C₆alkylene, C₂-C₆alkenylene,C₂-C₆alkynylene, —(CH₂)_(m)-G³-(CH₂)_(q)—, —(CH₂)_(m)-G⁴-(CH₂)_(q)—, or-G⁵-C≡C—; wherein the C₁-C₆alkylene, C₂-C₆alkenylene, andC₂-C₆alkynylene are optionally substituted with 1, 2, 3, or 4 fluorosubstituents; and wherein m and q are each independently 0, 1, 2, or 3and m+q=0, 1, 2, 3, or 4; G³ is O, C(O), S, S(O), S(O)₂, or NR⁹; whereinR⁹ is H, C₁-C₄ alkyl, or C₁-C₄alkylcarbonyl; G⁴ is

wherein G⁴ is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; G⁵ is

wherein G⁵ is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; R⁷ is C₃-C₈cycloalkyl, aryl,heteroaryl, or heterocyclyl; wherein R⁷ is optionally substituted with1, 2, 3, or 4 substituents selected from the group consisting ofC₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy; and r is 0 or
 1. 18.The method of claim 1 comprising administering a compound selected fromthe group consisting of: methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;7-((5R)-3,3-difluoro-5-((3S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;7-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl7-((5R)-3,3-difluoro-5-((E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((R)-3,3-difluoro-5-((R,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoate;7-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((R,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid; methyl4-(2-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;methyl4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;methyl4-(2-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;methyl4-(2-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxydec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid; methyl4-(2-((5R)-3,3-difluoro-5-((E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;methyl4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;methyl4-(2-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate;4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;4-(2-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((5R)-3,3-difluoro-5-((3R,E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyldec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxynon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxydec-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((5R)-3,3-difluoro-5-((E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((R,E)-3-hydroxyoct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((R)-3,3-difluoro-5-((S,E)-3-hydroxy-7-phenylhept-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((S)-3,3-difluoro-5-((S)-3-hydroxy-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((S)-3,3-difluoro-5-((S)-3-hydroxy-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)heptanoate;7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)heptanoate;7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-8-phenyloctyl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)heptanoate;methyl7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)heptanoate;7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((S)-3,3-difluoro-5-((3R,4R)-3-hydroxy-4-methyl-9-phenylnonyl)-2-oxopyrrolidin-1-yl)heptanoicacid; methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;methyl5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;5-(3-((R)-3,3-difluoro-5-((3S,4R,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;(R)-1-(6-(1H-tetrazol-5-yl)hexyl)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)pyrrolidin-2-one;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)-N-ethylheptanamide;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)-N-(methylsulfonyl)heptanamide;7-((S)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,Z)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;3-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)benzoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)hept-5-ynoicacid;(Z)-7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)hept-5-enoicacid;5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)prop-1-yn-1-yl)thiophene-2-carboxylicacid;4-((2-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)ethyl)thio)butanoicacid;7-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)heptanoicacid;5-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid;4-(2-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)ethyl)benzoicacid;3-(3-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)propyl)benzoicacid;4-((2-((S)-3,3-difluoro-5-((3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl)-2-oxopyrrolidin-1-yl)ethyl)thio)butanoicacid;7-((R)-3,3-difluoro-5-((3S,4S)-3-hydroxy-4-methyl-7-phenylhept-1-yn-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-4-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-5-phenylpent-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-6-phenylhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-8-phenyloct-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-9-phenylnon-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-5-((3S,4S,E)-7-cyclohexyl-3-hydroxy-4-methylhept-1-en-1-yl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-(naphthalen-2-yl)hept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-(naphthalen-1-yl)hept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-7-(3-fluorophenyl)-3-hydroxy-4-methylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-(m-tolyl)hept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-5-((3S,4S,E)-7-(3-chlorophenyl)-3-hydroxy-4-methylhept-1-en-1-yl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-7-(3-methoxyphenyl)-4-methylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-7-(3-(methoxymethyl)phenyl)-4-methylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-6-(phenylthio)hex-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-6-phenoxyhex-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-5-((3S,4S,E)-4-ethyl-3-hydroxy-7-phenylhept-1-en-1-yl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3R,4R,E)-3-hydroxy-4-isopropyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((3R,4S,E)-3-hydroxy-7-phenyl-4-(trifluoromethyl)hept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-5-((R,E)-4,4-difluoro-3-hydroxy-7-phenylhept-1-en-1-yl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-3,3-difluoro-5-((R,E)-3-hydroxy-4-methylene-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid;7-((R)-5-((R,E)-4-(difluoromethylene)-3-hydroxy-7-phenylhept-1-en-1-yl)-3,3-difluoro-2-oxopyrrolidin-1-yl)heptanoicacid; and7-((R)-3,3-difluoro-5-((R,E)-3-hydroxy-3-(1-(3-phenylpropyl)cyclobutyl)prop-1-en-1-yl)-2-oxopyrrolidin-1-yl)heptanoicacid; or a pharmaceutically acceptable salt thereof.
 19. The method ofclaim 1 further comprising administration of the compound of formula(Ia), or a pharmaceutically acceptable salt thereof, with apharmaceutically acceptable carrier.
 20. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compound offormula (Ia)

or a pharmaceutically acceptable salt thereof, wherein: L¹ is a)C₃-C₇alkylene, C₃-C₇alkenylene, or C₃-C₇alkynylene, wherein theC₃-C₇alkylene, C₃-C₇alkenylene, or C₃-C₇alkynylene are each optionallysubstituted with 1, 2, 3, or 4 fluoro substituents; b)—(CH₂)_(t)-G-(CH₂)_(p)—; wherein t is 0, 1, or 2, D is 0, 1, 2, or 3,and t+p=0, 1, 2, 3, or 4; or c) —(CH₂)_(n)-G¹-(CH₂)_(p)—,—(CH₂)_(n)-G₂-(CH₂)_(p)—, —(CH₂)_(n)—C≡C-G²-, or—(CH₂)_(n)—C(R¹³)═C(R¹³)-G²-, wherein n is 1, 2, 3, 4, or 5, D is 0, 1,2, or 3, and n+p=1, 2, 3, 4, 5, or 6; G is

G¹ is O, C(O), S, S(O), S(O)₂, or NR⁸; wherein R⁸ is H, C₁-C₄ alkyl, orC₁-C₄alkylcarbonyl; G² is

wherein G² is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; R¹ is COOR¹⁰, CONR¹⁰R¹¹,CH₂OR¹⁰, SO₃R¹⁰, SO₂NR¹⁰R¹¹, PO(OR¹⁰)₂, or tetrazol-5-yl; R¹⁰ is H,C₁-C₄ alkyl, or aryl; R¹¹ is H, C₁-C₄ alkyl, COR¹², OR¹⁰, or SO₂R¹²; R¹²is C₁-C₄ alkyl; R¹³, at each occurrence, is independently H orC₁-C₄alkyl; L⁴ is —C(R²)₂—C(R³)₂—, —C(R²)═C(R³)—, —C≡C—, or

wherein R² and R³ are each H, CH₃, fluoro, or choro; L² is —CH₂— or abond; R⁴ and R⁵ are each independently H, F, CF₃, or C₁-C₄ alkyl; or R⁴and R⁵ together with the carbon to which the are attached form a C₃-C₅cycloalkyl,

R⁶ is aryl, heteroaryl, C₃-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, C₃-C₁₀haloalkynyl, or L³-R⁷; whereinthe aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₄alkyl,C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy; and—C₁-C₃alkylene-C₁-C₃alkoxy; and wherein the C₃-C₁₀alkyl, C₃-C₁₀alkenyl,C₃-C₁₀alkynyl, C₃-C₁₀haloalkyl, C₃-C₁₀haloalkenyl, and C₃-C₁₀haloalkynylare optionally substituted with a substituent selected from the groupconsisting of COOR^(10′), CONR^(10′)R^(11′), CH₂OR^(10′), SO₃R^(10′),SO₂NR^(10′)R^(11′), PO(OR^(10′))₂, and tetrazol-5-yl; R^(10′) is H,C₁-C₄ alkyl, or aryl; R^(11′) is H, C₁-C₄ alkyl, COR^(12′), OR^(10′), orSO₂R^(12′); R^(12′) is C₁-C₄ alkyl; L³ is C₁-C₆alkylene,C₂-C₆alkenylene, C₂-C₆alkynylene, —(CH₂)_(m)-G³-(CH₂)_(q)—,—(CH₂)_(m)-G⁴-(CH₂)_(q)—, or -G⁵-C≡C—; wherein the C₁-C₆alkylene,C₂-C₆alkenylene, and C₂-C₆alkynylene are optionally substituted with 1,2, 3, or 4 fluoro substituents; and wherein m and g are eachindependently 0, 1, 2, or 3 and m+g=0, 1, 2, 3, or 4; G³ is O, C(O), S,S(O), S(O)₂, or NR⁹; wherein R⁹ is H, C₁-C₄ alkyl, orC₁-C₄alkylcarbonyl; G⁴ is

wherein G⁴ is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; G⁵ is

wherein G⁵ is optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of C₁-C₄alkyl, C₁-C₃haloalkyl, cyano,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkoxy; R⁷ is C₃-C₈cycloalkyl, aryl,heteroaryl, or heterocyclyl; wherein R⁷ is optionally substituted with1, 2, 3, or 4 substituents selected from the group consisting ofC₁-C₄alkyl, C₁-C₃haloalkyl, cyano, halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, and —C₁-C₃alkylene-C₁-C₃alkoxy; r is 0 or 1; and s is 0or
 1. 21-22. (canceled)